U.S. patent application number 17/228309 was filed with the patent office on 2021-08-05 for ophthalmic composition for treatment of dry eye disease.
The applicant listed for this patent is NOVALIQ GMBH. Invention is credited to Sonja KROSSER, Chiara Silvana LEO, Alice MEIDES, Thomas SCHLUTER.
Application Number | 20210236591 17/228309 |
Document ID | / |
Family ID | 1000005555949 |
Filed Date | 2021-08-05 |
United States Patent
Application |
20210236591 |
Kind Code |
A1 |
LEO; Chiara Silvana ; et
al. |
August 5, 2021 |
OPHTHALMIC COMPOSITION FOR TREATMENT OF DRY EYE DISEASE
Abstract
The invention provides ophthalmic compositions comprising about
0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for
use in the topical treatment of dry eye disease. The invention
further provides kits comprising such compositions for the same
use.
Inventors: |
LEO; Chiara Silvana;
(Heidelberg, DE) ; KROSSER; Sonja; (Heidelberg,
DE) ; SCHLUTER; Thomas; (Heidelberg, DE) ;
MEIDES; Alice; (Heidelberg, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVALIQ GMBH |
Heidelberg |
|
DE |
|
|
Family ID: |
1000005555949 |
Appl. No.: |
17/228309 |
Filed: |
April 12, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/EP2019/077578 |
Oct 11, 2019 |
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17228309 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/13 20130101;
A61K 9/0048 20130101; A61P 27/04 20180101; A61F 9/0008
20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 9/00 20060101 A61K009/00; A61P 27/04 20060101
A61P027/04; A61F 9/00 20060101 A61F009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 12, 2018 |
EP |
18200154.5 |
Oct 24, 2018 |
EP |
18202263.2 |
Apr 5, 2019 |
EP |
19167551.1 |
Claims
1-16. (canceled)
17. A kit comprising: (a) a container for holding an ophthalmic
composition; (b) a drop dispenser adapted for dispensing a single
drop of the composition of about 8 to 10 .mu.l volume, wherein the
drop dispenser is mounted, fixed or connected to the container for
holding the ophthalmic composition; and (c) instructions for use of
the ophthalmic composition in a method of treating
keratoconjunctivitis sicca (dry eye disease); wherein the
ophthalmic composition comprises 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane and up to about 1.0% (w/w) ethanol;
and wherein the method recited in the instructions comprises the
step of topically administering a dose of a single drop of the
composition twice daily to an eye of a patient, wherein said
patient has at least one eye with a total ocular surface disease
index score (OSDI) of equal or greater than 55; and wherein said
patient has at least one eye with: (i) a total corneal fluorescein
staining of at least 11 (NEI scale); or (ii) a central corneal
fluorescein staining score of 2 to 3 (NEI scale); or (iii) a total
lissamine green conjunctival staining score in the range of 2 to 6;
or (iv) an unanesthetized Schirmer's test score in the range of 2
to 8 mm; or (v) any combination of (i) to (iv); or (vi) any
combination of (i) to (iv), with the specified values in both
eyes.
18. The kit according to claim 17, wherein the container holds
multiple, or a plurality of doses of the composition.
19. A method for improving the visual function, or predicting the
improvement of visual function, of a patient suffering from dry eye
disease (keratoconjunctivitis sicca), wherein the patient is
characterized by having at least one eye with a total corneal
fluorescein staining score of at least 11 (NEI scale) at baseline,
wherein the improvement in visual function in the patient is
characterized by a reduction in the total corneal fluorescein
staining score (NEI scale) by three or more units, and wherein the
method comprises the step of administering to the eye of the
patient a composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)-pentane and up to about 1% (w/w) ethanol;
wherein said composition is administered twice per day per eye, at
a dose of a single drop per eye of a volume of about 8 to 12
.mu.L.
20. The method of claim 19, wherein the method comprises
administering the composition for a period of at least four
weeks.
21. The method of claim 19, wherein the improvement of visual
function is further characterized by an improvement in the number
of words read per minute in an international reading speed texts
(IReST).
22. The method of claim 19, wherein the improvement of visual
function is further characterized by an improvement of any one or a
combination of blurred vision, reading, driving at night, working
with a computer, working at an automatic teller machine, reading at
low contrast, and reading at low print size.
23. The method of claim 19, wherein the composition is administered
twice per day per eye, at a dose of a single drop per eye of a
volume of about 8 to 10 .mu.L.
24. The method of claim 19, wherein the patient has at least one
eye with a total ocular surface disease index score (OSDI) of equal
or greater than 55, and at least one eye with: (i) a total corneal
fluorescein staining score at least 11 (NEI scale); or (ii) a
central corneal fluorescein staining value of about 1 to 3 (NEI
scale); or (iii) a total lissamine green conjunctival staining
score in the range of 2 to 6; or (iv) an unanesthetized Schirmer's
test score in the range of 4 to 6 mm; or (v) any combination of (i)
to (iv); or (vi) any combination of (i) to (iv), with the specified
values in both eyes.
25. The method according to claim 24, wherein the central corneal
fluorescein staining value is about 3 (NEI scale).
26. The method according to claim 24, wherein the lissamine green
conjunctival staining score is in the range of 3 to 5.
27. The method according to claim 19, wherein a decrease of the
total corneal fluorescein staining score (NEI scale) by 3 or more
units is indicative for improvement of visual function.
28. A method of treating and/or ameliorating the symptoms of
dryness associated with keratoconjunctivitis sicca (dry eye
disease) in a patient in need thereof, wherein the method comprises
topically administering an ophthalmic composition comprising 0.1%
(w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane, and up
to about 1.0% (w/w) ethanol, wherein the composition is
administered in a dose of a single drop per eye in a volume of
about 8 to 10 .mu.L, twice per day per eye; wherein the composition
is effective in reducing the frequency of the symptom of dryness
and/or the severity of dryness within 4 weeks after start of
treatment; and wherein the patient has at least one eye with a
total ocular surface disease index score (OSDI) of equal or greater
than 55; and wherein the patient has at least one eye with: (i) a
total corneal fluorescein staining score of at least 11 (NEI
scale); or (ii) a central corneal fluorescein staining value of
about 2 to 3 (NEI scale); or (iii) a lissamine green conjunctival
staining score in the range of 2 to 6; or (iv) an unanesthetized
Schirmer's test score in the range of 2 to 8 mm; or (v) any
combination of (i) to (iv); or (vi) any combination of (i) to (iv),
with the specified values in both eyes.
29. The method of claim 28, wherein the effectiveness in reduction
in the frequency of dryness or the severity of dryness, or
combination thereof is determined by visual analog scale (VAS)
testing on a scale of 0 to 100%, wherein frequency of dryness and
awareness of dry eye symptoms are measured on a scale of 0 to 100%
as the percentage of time said symptom(s) is experienced by a
patient and wherein the severity of dryness is measured on a scale
of 0 to 100% as the percentage level of discomfort experienced by
the patient.
30. The method of claim 28, wherein the composition is effective in
reducing the frequency of dryness and/or the severity of dryness by
at least 25%, preferably by at least 30% after four weeks, as
determined by visual analog scale (VAS) testing on a scale of 0 to
100%, wherein frequency of dryness and awareness of dry eye
symptoms are measured on a scale of 0 to 100% as the percentage of
time said symptom(s) is experienced by a patient and wherein the
severity of dryness is measured on a scale of 0 to 100% as the
percentage level of discomfort experienced by the patient.
31. The method of claim 28, wherein the method is effective in
reducing in a patient the total corneal fluorescein staining score
in at least one eye (sum of inferior, superior, central, nasal, and
temporal staining scores; NEI scale), by at least 3 grades after 4
weeks of treatment, preferably in at least 50% of the patients
undergoing treatment.
32. The method of claim 28, wherein the dry eye disease is
aqueous-deficient dry eye disease.
33. The method of claim 28, wherein the dry eye disease is
evaporative dry eye disease.
34. The method of claim 28, wherein the patient is non-responsive,
or insufficiently responsive, to treatment with aqueous ophthalmic
eye drop compositions.
35. A method of treating keratoconjunctivitis sicca (dry eye
disease), the method comprising the step of topically administering
an ophthalmic composition comprising 0.1% (w/v) cyclosporine
dissolved in 1-(perfluorobutyl)pentane and up to about 1.0% (w/w)
ethanol to an eye of a patient; wherein the composition is
administered twice per day per eye, and as a single drop having a
volume of about 8 to 10 .mu.L; wherein the patient has at least one
eye with a total ocular surface disease index (OSDI) score of equal
or greater than 55; and wherein the patient has at least one eye
with any one or combination of criteria selected from the group
consisting of: (i) a total corneal fluorescein staining score of at
least 11 (NEI scale); (ii) a central corneal fluorescein staining
value of about 2 to 3 (NEI scale); (iii) a total lissamine green
conjunctival staining score in the range of 2 to 6; (iv) an
unanesthetized Schirmer's test score in the range of 4 to 6 mm; and
(v) any one or combination of (i) to (iv); or (vi) any combination
of (i) to (iv), with the specified values in both eyes.
36. The method of claim 35, wherein treatment is effective in
reducing ocular surface damage selected from ocular surface damage
of the central corneal region and ocular surface damage of the
inferior corneal region.
37. The method of claim 35, wherein the dry eye disease is
aqueous-deficient dry eye disease.
38. The method of claim 35, wherein the dry eye disease is
evaporative dry eye disease.
39. The method of claim 35, wherein the patient is non-responsive,
or insufficiently responsive to treatment with aqueous ophthalmic
eye drop compositions (e.g., aqueous cyclosporin emulsion eye
drops).
40. The method of claim 35, wherein the patient has a history of
keratoconjunctivitis sicca (dry eye disease) in one or both eyes
for at least six months.
41. The method of claim 35, wherein the patient has at least one
eye, or both eyes with any one or combination of: (i) a central
corneal fluorescein staining (NEI scale) score of 2 or higher; (ii)
an inferior corneal fluorescein staining (NEI scale) score of 2 or
higher; and (iii) a total corneal fluorescein staining (NEI scale)
score of 11 or higher.
Description
BACKGROUND OF THE INVENTION
[0001] Keratoconjunctivitis sicca, also known as dry eye disease or
dysfunctional tear syndrome, is today understood as a
multifunctional disorder of the tear film and of the ocular surface
which results in discomfort, visual disturbance, and often even in
ocular surface damage caused by tear film instability. Estimates of
the prevalence of dry eye vary considerably, depending on the
criteria used to define the disease, but in the U.S., it has been
estimated that as many as 3.2 million women and 1.7 million men
over the age of 50 have dry eye, with a projected 40% increase in
number of patients affected by 2030.
[0002] A pharmacological treatment option for dry eye disease is
cyclosporine. Cyclosporine is available, at least in the US as an
approved medicine in the form of an ophthalmic (o/w) emulsion
(Restasis.RTM.). This product is indicated to increase tear
production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with
keratoconjunctivis sicca.
[0003] WO2011/073134 A1 discloses pharmaceutical compositions in
the form of solutions comprising cyclosporine and a semifluorinated
alkane as a liquid vehicle which may be administered to the eye of
a patient, such as for the treatment of keratoconjunctivitis sicca,
for instance compositions comprising cyclosporine in
semifluorinated alkane 1-(perfluorobutyl)pentane (F4H5) in the
presence of ethanol as a co-solvent.
[0004] Gehlsen et al. (Investigative Ophthalmology & Visual
Science June 2015, Vol. 56, 319) describes a study to test the use
of CsA in (F4H5) for topical therapy in a mouse model of
experimental dry eye disease. Gehlsen et al describes that in the
study, topical therapy was performed on mice with induced
experimental dry eye disease 3.times./day (5 .mu.L/eye). Gehlsen et
al. however does not disclose a treatment or dosing regimen for the
treatment of dry eye disease in human subjects.
[0005] WO2018/115097 describes a dosing regimen for the treatment
of patients with dry eye disease, based on ophthalmic compositions
comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane. This document however does not disclose
a targeted treatment in respect of specific symptoms associated
with dry eye disease and the frequency of their occurrence. The
method of treatment also does not disclose a composition for use in
a treatment of patients meeting a specific set of dry eye disease
signs and symptoms.
[0006] Accordingly there is still a need for means and method for
treating patients meeting certain criteria for dry eye disease, as
well as for treating patients for which certain symptoms of dry eye
disease is particularly prevalent. It is thus an object of the
present invention to provide composition for use which is effective
in addressing these specific aspects. Further objects of the
invention will be clear on the basis of the following description
of the invention, examples and claims.
SUMMARY OF THE INVENTION
[0007] In a first aspect, the invention relates to an ophthalmic
composition comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane for use in a method of treating
keratoconjunctivitis sicca (dry eye disease), wherein the method
comprises a step of topically administering the composition to an
eye of a patient, and wherein the patient has a total ocular
surface disease index (OSDI) score of equal or greater than 45. In
other embodiments, the patient has a total ocular surface disease
index (OSDI) score of equal or greater than 55.
[0008] In a second aspect, the invention relates to an ophthalmic
composition comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane for use in: a) a method of treating
and/or ameliorating the symptoms associated with
keratoconjunctivitis sicca (dry eyes), wherein the symptoms are
dryness and blurred vision; and/or b) for use in a method of
treating and/or ameliorating the awareness of symptoms of dry eyes
and the frequency of dryness.
DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1. Total ocular surface disease index (OSDI)--depicted
is the change from baseline of the total OSDI score (mean) at 2
weeks, 4 weeks, 8 weeks and 12 weeks of treatment (2 times per day)
with vehicle (F4H5; N=90) and CyclASol 0.1% Ophthalmic Solution
(clear ophthalmic solution of Cyclosporine A dissolved in
1-(perfluorobutyl)pentane, with 1.0% w/w ethanol; N=79), in
subjects with a baseline total OSDI of 45 or greater.
[0010] FIG. 2. Total ocular surface disease index (OSDI)--depicted
is the change from baseline of the total OSDI score (mean) at 2
weeks, 4 weeks, 8 weeks and 12 weeks of treatment (two times per
day) with vehicle (F4H5; N=55) and CyclASol 0.1% Ophthalmic
Solution (clear ophthalmic solution of Cyclosporine A dissolved in
1-(perfluorobutyl)pentane, with 1.0% w/w ethanol; N=41), in
subjects with a baseline total OSDI of 55 or greater.
[0011] FIG. 3. VAS symptom improvements. Depicted is the mean
change from baseline (Visit 1) after 4 weeks of the VAS score in
study subjects administered (2 times per day) with vehicle (F4H5;
N=165) and CyclASol 0.1% Ophthalmic Solution (N=160; clear
ophthalmic solution of Cyclosporine A dissolved in
1-(perfluorobutyl)pentane, with 1.0% w/w ethanol) for: blurred
vision, awareness of symptoms of dry eye, frequency of dryness,
severity of dryness, and combined frequency and severity of
dryness.
[0012] FIG. 4. Total ocular surface disease index (OSDI)--depicted
is the change from baseline of the total OSDI score (mean) at 2
weeks, 4 weeks, 8 weeks and 12 weeks of treatment (2 times per day)
with vehicle (F4H5; N=166) and CyclASol 0.1% Ophthalmic Solution
(clear ophthalmic solution of Cyclosporine A dissolved in
1-(perfluorobutyl)pentane, with 1.0% w/w ethanol; N=162), for the
entire population of subjects.
[0013] FIG. 5. Total corneal fluorescein staining (NEI
scale)-depicted is the change from baseline of the total corneal
fluorescein staining (mean) at 2 weeks, 4 weeks, 8 weeks and 12
weeks of treatment (2 times per day) with vehicle (F4H5; N=165) and
CyclASol 0.1% Ophthalmic Solution (clear ophthalmic solution of
Cyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0%
w/w ethanol; N=160), for the entire population of subjects. Error
bars show standard error of the mean (SEM).
[0014] FIG. 6. Total corneal fluorescein staining responder
analysis (.gtoreq.3 grades improvement) after 4 weeks of treatment.
Compared are the proportions of subjects, respectively treated with
CyclAsol 0.1% and vehicle, with a grades improvement in the total
corneal fluorescein staining (tCFS).
[0015] FIG. 7. Central corneal fluorescein staining (NEI scale)
responder analysis (.gtoreq.1 grade improvement) after 4 weeks of
treatment. Compared are the proportions of subjects, respectively
treated with CyclAsol 0.1% and vehicle, with a 1 grade improvement
in the central corneal fluorescein staining (cCFS).
[0016] FIG. 8. Conjunctival lissamine green staining responder
analysis (.gtoreq.2 grades improvement) after 12 weeks of
treatment. Compared are the proportions of subjects, respectively
treated with CyclAsol 0.1% and vehicle, with a .gtoreq.2 grades
improvement in the conjunctival lissamine green staining.
[0017] FIG. 9. Conjunctival lissamine green staining (change from
baseline on Oxford scale)-depicted is the change from baseline of
the conjunctival lissamine green staining value (mean) at 4 weeks
and 12 weeks of treatment (2 times per day) with vehicle (F4H5) and
CyclASol 0.1% Ophthalmic Solution (clear ophthalmic solution of
Cyclosporine A dissolved in 1-(perfluorobutyl)pentane, with 1.0%
w/w ethanol), for the entire population of subjects. Error bars
show the standard error of the mean (SEM).
[0018] FIG. 10. International Reading Speed Texts (IResT) critical
print size--depicted is the number of words read per minute for a)
all the patients at baseline (N=322); b) the tCFS non responder
group (N=172) after four weeks; and c) the tCFS responder group
(N=150) after four weeks, wherein tCFS responders are subjects
whose tCFS score decreased of 3 or more units (NEI) after four
weeks.
[0019] FIG. 11. International Reading Speed Texts (IResT) critical
print size--depicted is the number of words read per minute for the
CyclASol group of patients at baseline (N=157), the CyclASol tCFS
non responders after four weeks (N=74) and the CyclASol tCFS
responders after four weeks (N=83), respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention relates to, in a first aspect, an
ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane for use in a method of treating of
keratoconjunctivitis sicca (dry eye disease), wherein the method
comprises a step of topically administering the composition to an
eye of a patient, and wherein the patient has a total ocular
surface disease index (OSDI) score of equal or greater than 45.
[0021] Dry eye disease (also abbreviated as DED, and which also may
be known as keratoconjunctivitis sicca, dysfunctional tear syndrome
or dry eye syndrome) is a complex disease that results in symptoms
of discomfort, visual disturbance, and tear film instability, and
which creates potential for damage of the ocular surface. It may be
accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface. A patient having
keratoconjunctivitis sicca may experience any one of, or a
combination of tear hyperosmolarity, tear film instability or
abnormalities in the lipid layer composition of the tear film.
[0022] Two major categories of keratoconjunctivitis sicca or dry
eye disease (DED) are distinguished today, which are
aqueous-deficient DED and evaporative DED. Within the class of
aqueous-deficient forms of DED, two major subtypes may be
differentiated, Sjogren and non-Sjogren.
[0023] Sjogren syndrome patients suffer from autoimmune disorders
in which the lacrimal glands are invaded by activated T-cells,
which leads not only to dry eye disease but also to a dry mouth
condition. The Sjogren syndrome can be a primary disease or can
result from other autoimmune diseases, such as systemic lupus
erythrematosus or rheumathroid arthritis. Non-Sjogren patients
suffering from an aqueous-deficient DED usually have a lacrimal
gland insufficiency, lacrimal duct obstruction or reflex
hyposecretion.
[0024] The second major class, evaporative dry eye disease, is also
somewhat heterogeneous and can develop as a result of diverse root
causes. One of the major causes is meibomian gland disease or
dysfunction, eyelid aperture disorders, blink disorders (as in
Parkinson's disease) or ocular surface disorders (as in allergic
conjunctivitis).
[0025] Symptoms of dry eye disease may include, but are not limited
to, any one, or combination of, the following: a dry, scratchy,
gritty, or sandy feeling in the eye; foreign body sensation; pain
or soreness; stinging or burning; itching; increased blinking; eye
fatigue; photophobia; blurry vision; redness; mucus discharge;
contact lens intolerance; and excessive reflex tearing. It is
understood that not all patients suffering from dry eye disease may
exhibit all of these symptoms simultaneously.
[0026] Subjects suffering from dry eye disease may experience
symptoms which individually, or collectively, such as blurring,
pain, irritation which may contribute to visual impairment or
difficulties which can be reflected by a negative effect on the
subject's performance in functional tasks where visual performance
and acuity may be essential. Dry eye disease may also lead, or
contribute to corneal surface damage for example to the central
cornea.
[0027] As understood herein, the term "dry eye disease"
individually may refer to any one or combination of the subtypes or
categories, or root causes as described herein and that any symptom
or aspect or pathophysiological consequences of dry eye disease may
be addressed.
[0028] The severity of dry eye disease in subjects or patients can
be classified and scored using one or more, or a combination of
standard tests based on assessment of dry eye disease symptoms. For
example, the severity of dry eye disease may be determined using
tests based on the assessment of patient perception of ocular
symptoms and their effect on vision, based on questionnaires such
as the Ocular Surface Disease Index (OSDI) questionnaire, which is
a 12-item questionnaire focussed on symptoms of ocular irritation
associated with dry eye disease and their impact on daily
activities and lifestyle of the patient during the week preceding
their assessment.
[0029] The OSDI test is scored using a scale of 0 to 4 for each
question. For example, as part of the test patients may be asked
questions regarding problems with blurred vision during the last
week, and are asked to indicate, if applicable, either 0 for none
of the time, 1 for some of the time, 2 for half of the time, 3 for
most of the time or 4 for all of the time. The scores from the
questionnaire are totalled and assessed on a scale of 0 to 100,
with higher scores representing greater degree/severity and impact
of dry eye disease. In the context of the present invention, it has
been found that the compositions as defined are particularly
effective especially in the treatment of dry eye disease in
patients having at baseline, prior to commencement of treatment
with the composition, a total OSDI score of equal, or greater than
45; or patients with a total OSDI score of equal, or greater than
55.
[0030] The dry eye symptom visual analogue scale (VAS) is a test in
the form of a questionnaire, where subjects are asked to rate their
ocular symptoms (both eyes simultaneously) by placing a vertical
mark on the horizontal line to indicate the level of discomfort
from a scale of 0 to 100% with regards to dryness, sticky feeling,
burning/stinging, foreign body sensation, itching, blurred vision,
sensitivity to light, and pain, wherein 0 corresponds to "no
discomfort" while 100% corresponds to "maximal discomfort". The VAS
test also assesses the frequency in occurrence of dryness
experienced by the subject, as well as the percentage of time the
subject is aware of experiencing the symptoms of dry eye, (with 0
corresponding to `never` and 100% corresponding to `all of the
time`). The VAS test may be conducted at various time points to
assess the effectiveness and patient response in respect to impact
of therapy on these symptoms of dry eye disease.
[0031] Signs of dry eye disease in a patient's eye may also be
evaluated and determined using any combination of objective
clinical measures such as the Schirmer test type 1, fluorescein
staining and/or lissamine green staining of the cornea and
conjunctiva, and tear-film break up time (TFBUT, or TBUT) as a
measurement of tear quality. Therapeutic efficacy may also be
assessed by comparison of measurements for each or combination of
these clinical measures, obtained at various time points during a
given treatment period, also in combination or conjunction with any
of the symptom assessments described above.
[0032] In one embodiment of the invention described herein, the
subject or patient has, prior to treatment with the compositions
defined herein, a total OSDI scoring of equal or greater than 45,
or preferably equal or greater than 55, as well as, in at least one
eye, or alternatively both eyes, any one or combination of the
following:
i. a total corneal fluorescein staining score of .gtoreq.10
according to NEI grading (i.e. sum of scoring for the inferior,
superior, central, nasal, and temporal cornea regions equal to or
greater than 10); ii. a total lissamine green conjunctival score
(sum of temporal and nasal regions) of .gtoreq.2 according to the
Oxford scale; iii. a Schirmer's Test I score of between 1 mm and 10
mm or any combination thereof.
[0033] Cyclosporine is a pharmacological treatment option for dry
eye disease, which is available as a prescription medication, for
example, in the US in the form of an 0.05% ophthalmic (o/w)
emulsion (Restasis.RTM.). This product is indicated to increase
tear production in patients whose tear production is presumed to be
suppressed due to ocular inflammation associated with
keratoconjunctivis sicca. Restasis.RTM. is administered twice a day
in each eye approximately 12 hours apart. It is packaged in
single-vials. (Prescribing Information, Restasis.RTM.).
[0034] Cyclosporine (synonyms include cyclosporin A, CsA, or
ciclosporin) is a cyclic nonribosomal peptide comprising 11 amino
acids with the empirical formula C.sub.62H.sub.111N.sub.11O.sub.12
and molecular weight of 1202.61. It is an immunosuppressant drug
that is widely used in post-allergenic organ transplant, to reduce
the activity of the patient's immune system and thereby, the risk
of organ rejection. Cyclosporine is typically provided as a
colourless or white powder. Cyclosporine is thought to bind to the
cytosolic protein cyclophilin (immunophilin) of immunocompetent
lymphocytes, especially T-lymphocytes. This complex of cyclosporin
and cyclophilin inhibits calcineurin, which, under normal
circumstances, is responsible for activating the transcription of
interleukin 2. It also inhibits lymphokine production and
interleukin release and, therefore, leads to a reduced function of
effector T-cells.
[0035] The ophthalmic composition according to the present
invention employs, as a liquid vehicle for the cyclosporine, the
compound 1-(perfluorobutyl)pentane. 1-(perfluorobutyl)pentane is a
semifluorinated alkane with the chemical formula
F(CF.sub.2).sub.4(CH.sub.2).sub.5H. It is an inert, water-insoluble
liquid, with a density of 1.284 g/cm.sup.3 at 25.degree. C. and
refractive index of 1.3204 at 20.degree. C. Alternative
nomenclature for this compound includes F4H5, wherein F denotes a
linear perfluorinated alkane segment comprising 4 carbon atoms and
wherein H denotes a linear and non-fluorinated alkane hydrocarbon
segment of 5 carbon atoms. Preferably, the
1-(perfluorobutyl)pentane is substantially free of water.
[0036] In one embodiment, the ophthalmic composition for any one of
the uses according to the present invention may comprise or
consist, further to the cyclosporine featured in any one the
preferred concentrations of the invention, of at least about 97%
(w/w) or more preferably, of at least about 98% (w/w), or of at
least about 99% (w/w) of 1-(perfluorobutyl)pentane, based on the
total weight of the ophthalmic composition (final dosage form). In
another embodiment, the pharmaceutical composition for any one of
the uses according to the present invention may consist of, in
addition to the cyclosporine in an amount or concentration as
defined herein, from about 95.0 to about 99.99% (w/w), or about
96.0 to about 99.99% (w/w), or from about 98.0 to 99.99% (w/w), or
from about 99.999 to about 99.9999% (w/w) of
1-(perfluorobutyl)pentane, based on the total weight of the final
composition.
[0037] In another embodiment, the ophthalmic composition for any
one of the uses described herein for the present invention may
optionally further comprise 2-(perfluorobutyl)pentane. The
composition, in addition to 1-(perfluorobutyl)pentane, may
optionally comprise minor amounts of 2-(perfluorobutyl)pentane, of
up to 2% (w/w), or up to 1% (w/w), or up to 0.5% (w/w).
[0038] The concentration of cyclosporine in the ophthalmic
compositions for any one of the uses according to the invention is
0.1% (w/v) of the composition.
[0039] Unless otherwise indicated, the term "% (w/v)" denotes the
amount of a component of a composition as a weight percentage in
relation to the total volume of the composition (with `w` denoting
the weight and `v` denoting volume). For example 0.1% (w/v) would
correspond to 1.0 mg of a component in 1 mL of the composition.
Unless otherwise indicated, the term "% (w/w)" or wt % refers to
the amount of a component of a composition as a weight percentage
in relation to the total weight of the composition (with `w`
denoting weight).
[0040] The term `about` as used herein and in reference or
connection to a parameter, for example such as the concentration of
cyclosporine dissolved in the composition or the volume featured in
a single dose or applied liquid drop of the composition includes
the precise value as defined, as well as any value falling within
the degree of variability usually observed in measuring or
determining these parameters using the standard techniques and
equipment known in the art and field.
[0041] The ophthalmic composition as defined herein may be used for
the treatment of human subjects with dry eye disease, as well as
for any related conditions, or signs and symptoms associated
therewith.
[0042] In a first aspect, the present invention provides for the
following items: [0043] 1.1 An ophthalmic composition comprising
0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane for
use in a method of treating keratoconjunctivitis sicca (dry eye
disease), wherein the method comprises a step of topically
administering the composition to an eye of a patient, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 45. [0044] 1.2 Composition for use of 1.1,
wherein the patient has a total ocular surface disease index (OSDI)
score of equal or greater than 55. [0045] 1.3 The ophthalmic
composition for use of any one of the preceding items, wherein the
composition comprises up to about 1.0% (w/w) ethanol. [0046] 1.4
The ophthalmic composition for use of any one of the preceding
items, wherein the composition consists of 0.1% (w/v) cyclosporine,
1-(perfluorobutyl)pentane (F4H5) and up to 1.0% (w/w) ethanol.
[0047] 1.5 The composition for use of any of the preceding items,
wherein the ophthalmic composition is administered to the surface
of the cornea and/or conjunctiva in the form of a liquid drop.
[0048] 1.6 The composition for use in any of the preceding items,
wherein the composition is administered as a single drop having a
volume of about 8 to 11 .mu.L, preferably of about 8 to 10 .mu.L.
[0049] 1.7 The composition for use of any of the preceding items,
wherein the composition is administered in a dose of a single drop
per eye one time per day in volume of about 8-10 .mu.L. [0050] 1.8
The ophthalmic composition for use according to any one of the
preceding items, wherein the composition is administered as a
single drop having a volume of about 10 .mu.l. [0051] 1.9 The
ophthalmic composition for use of any one of the preceding items,
wherein the composition is administered twice a day per eye. [0052]
1.10 The composition for use in any of the preceding items, wherein
the composition is administered in a dose of a single drop per eye
twice per day in net volume of about 16-20 .mu.L. [0053] 1.11 The
composition for use according to any one of the preceding items,
wherein the dry eye disease is aqueous-deficient dry eye disease.
[0054] 1.12 The composition for use according to any of the
preceding items, wherein the dry eye disease is evaporative dry eye
disease. [0055] 1.13 The composition for use according to any of
the preceding items, wherein the patient is non-responsive, or
insufficiently responsive, to treatment with aqueous ophthalmic eye
drop compositions (e.g. aqueous cyclosporin emulsion eye drops).
[0056] 1.14 The composition for use of any of the preceding items,
wherein the time interval between topical administration of the
composition to the eye or eye surface of a first dose and a second
dose is at least 4 hours, or at least 6 hours, or at least 12
hours. [0057] 1.15 The composition for use of any of the preceding
items, wherein the duration of the treatment is for at least 2
weeks, or at least 4 weeks, or at least 6 weeks, or at least 8
weeks, or at least 12 weeks. [0058] 1.16 The composition for use of
any of the preceding items wherein the patient is a human patient.
[0059] 1.17 The composition for use of any of the preceding items,
wherein the patient is a female patient. [0060] 1.18 The
composition for use of any of the preceding items, wherein the
patient is a male patient. [0061] 1.19 The composition for use of
any of the preceding items, wherein the patient is aged 20-80 years
old at the time of treatment, e.g., 20-50 years old, or 20-70 years
old, or 30-80 years old, or 30-50 years old, or 30-70 years old, or
40-80 years old, or 40-60 years old, or 40-70 years old, or 50-80
years old, or 50-70 years old. [0062] 1.20 The composition for use
of any of the preceding items, wherein the patient suffers from a
co-morbidity, for example, conjunctivitis, stye, chalazion,
blepharitis, ectropion, eyelid laxity, eyelid edema, eyelid
dermatitis, punctate keratopathy, or ocular allergies, or any
combination thereof. [0063] 1.21 The composition for use of any of
the preceding items, wherein the patient suffers from
keratoconjunctivitis sicca which is caused by treatment of a
co-morbidity, for example, treatment with any one or more of:
isotretinoin, sedatives, diuretics, tricyclic antidepressants,
antihypertensives, anticholinergics, oral contraceptives,
antihistamine, nasal decongestants, beta-adrenergic antagonists,
phenothiazines, atropine opiates (e.g., morphine), optionally
wherein any such treatment is concurrent or previous, and further
optionally, wherein any such treatment is systemic (e.g., oral or
parenteral). [0064] 1.22 The composition for use of any of the
preceding items, wherein the patient suffers from
keratoconjunctivitis sicca which is caused by ocular surgical
intervention, for example, corneal surgery, refractive surgery,
LASIK surgery, cataract surgery, optionally wherein any such ocular
surgery is concurrent or previous. [0065] 1.23 The composition for
use of any of the preceding items, wherein the patient is
concomitantly under treatment with another topical ophthalmic
medication, for example, an antibiotic, antifungal, corticosteroid,
another immunosuppressant, sympathomimetic, anesthetic,
antihistamine, or any combination thereof. [0066] 1.24 The
composition for use of any of the preceding items, wherein the
patient is a contact lens wearer. [0067] 1.25 The composition for
use of any of the preceding items, wherein the patient was
unresponsive or insufficiently response to previous treatment for
keratoconjunctivitis sicca (dry eye disease). [0068] 1.26 The
composition for use of 1.25, wherein said previous treatment
comprises one or more of the following treatment methods: topical
aqueous immunosuppressant administration, (e.g., topical aqueous
ciclosporin), topical corticosteroid administration, or topical
aqueous artificial tears administration. [0069] 1.27 The
composition for use of any of the preceding items, wherein the
patient has at least one eye with a total corneal fluorescein
staining score at least equal or higher than 10. [0070] 1.28 The
composition for use of any of the preceding items, wherein the
patient has at least one eye with any one or combination of
criteria (e.g. signs of dry eye disease) selected from the group
consisting of: [0071] i. A total lissamine green conjunctival score
(sum of temporal and nasal regions) of .gtoreq.2 according to the
Oxford scale; [0072] ii. a total corneal fluorescein staining (NEI
scale) of .gtoreq.10 (i.e. sum of inferior, superior, central,
nasal and temporal regions); [0073] iii. an unanesthetized
Schirmer's Test score between 1 mm and 10 mm. [0074] 1.29 The
composition for use according to item 1.28, wherein the patient has
at least one eye (i.e. the same eye) which meets criteria (i), (ii)
and (iii). [0075] 1.30 The composition for use according to any one
of the preceding items, wherein the patient has at least one eye,
or both eyes with any one or combination of: [0076] i. a central
corneal fluorescein staining (NEI scale) score of 2 or higher,
[0077] ii. an inferior corneal fluorescein staining (NEI scale)
score of 2 or higher, [0078] iii. a total corneal fluorescein
staining (NEI scale) score of 11 or higher. [0079] 1.31 The
composition for use of any of the preceding items, wherein the
patient has a history of keratoconjunctivitis sicca (dry eye
disease) in one or both eyes for at least six months. [0080] 1.32
The composition for use of any of the preceding items, wherein the
composition is effective in reducing one or more signs and/or
symptoms of keratoconjunctivitis sicca (dry eye disease),
preferably wherein the one or more signs and/or symptoms is
selected from ocular surface damage. [0081] 1.33 The composition
for use of any of the preceding items, wherein the composition is
effective in reducing the one or more signs and/or symptoms of
keratoconjunctivitis sicca (dry eye disease) within 2 weeks, within
4 weeks, or within 8 weeks after first administration of the
composition/commencement of treatment. [0082] 1.34 The composition
for use in in any of the preceding items, wherein the composition
is effective in reducing ocular surface damage. [0083] 1.35 The
composition for use according to 1.32 to 1.34, wherein the ocular
surface damage is selected from the group consisting of: [0084] i.
surface damage of the total corneal region; [0085] ii. surface
damage of the central corneal region; [0086] iii. surface damage of
the nasal corneal region; [0087] iv. surface damage of the temporal
corneal region; [0088] v. surface damage of the inferior corneal
region; and [0089] vi. combinations thereof. [0090] 1.36 The
composition for use of 1.35, wherein the ocular surface damage is
selected from ocular surface damage in the central corneal region
and ocular surface damage of the inferior corneal region. [0091]
1.37 The composition for use of 1.32 to 1.36 wherein the reduction
of ocular surface damage is determined by corneal fluorescein
staining (NEI scale). [0092] 1.38 The composition for use of 1.37,
wherein the corneal fluorescein staining method is selected from
the group consisting of: [0093] iv. total corneal fluorescein
staining; [0094] v. central corneal fluorescein staining; [0095]
vi. nasal corneal fluorescein staining; [0096] vii. temporal
fluorescein staining; [0097] viii. inferior corneal fluorescein
staining; and [0098] ix. any combination thereof. [0099] 1.39 The
composition for use of 1.32 to 1.38, wherein the treatment is
effective in reducing the total corneal fluorescein staining score
(sum of inferior, superior, central, nasal, and temporal staining
scores; NEI scale) by an integer of at least 2, or by at least 3
points, optionally within a treatment period of at least 8 weeks,
or at least 12 weeks. [0100] 1.40 The composition for use of any of
the preceding items, wherein the composition is effective in
treating one or more ocular symptoms of keratoconjunctivitis sicca
(dry eye disease) selected from (x) dryness, (xi) sticky feeling,
(xii) burning/stinging, (xiii) foreign body sensation, (xiv)
itching, (xv) blurred vision, (xvi) sensitivity to light, (xvii)
pain, and (xviii) any combination thereof. [0101] 1.41 The
composition for use of any of the preceding items, wherein the
composition is effective in reducing the (xix) frequency of
dryness, (xx) awareness of symptoms of dry eye and (xxi) the
severity of dryness and (xxi) any combination thereof. [0102] 1.42
The composition for use of item 1.41, wherein the composition is
effective in reducing the severity of dryness or the frequency of
dryness or the combination thereof. [0103] 1.43 The composition for
use of any preceding items, wherein the method of treatment
comprises the reduction of ocular surface damage, e.g. ocular
surface damage of the cornea, or ocular surface damage selected
from: i. surface damage of the total corneal region; ii. surface
damage of the central corneal region; iii. surface damage of the
nasal corneal region; iv. surface damage of the temporal corneal
region; v. surface damage of the inferior corneal region; and vi.
combinations thereof [0104] 1.44 The composition for use of item
1.43, wherein the ocular surface damage is selected from ocular
surface damage in the central corneal region and ocular surface
damage of the inferior corneal region. [0105] 1.45 The composition
for use of item 1.43-1.44 wherein the ocular surface damage is
determined by corneal fluorescein staining (NEI scale). [0106] 1.46
The composition for use of any of the preceding items, wherein the
patient has at least one eye with any one or combination of
criteria selected from the group consisting of: [0107] a total
corneal fluorescein staining value in the range of 10 to 15,
preferably 10 to 13 (NEI scale); [0108] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale);
preferably 2 to 3 (NEI scale); [0109] a total lissamine green
conjunctival staining score in the range of 2 to 6, preferably 3 to
5; [0110] an unanesthetized Schirmer's test score in the range of 2
to 8 mm. [0111] 1.47 The composition for use of any of the
preceding items, wherein the patient does not suffer from meibomian
gland dysfunction and/or blepharitis. [0112] 1.48 The composition
for use of any of the preceding items, wherein the patient has an
unanesthetized Schirmer's Test score in the range of 3 to 7 mm,
preferably in the range of 4 to 6 mm, more preferably of about 5
mm. [0113] 1.49 The composition for use of any of the preceding
items, wherein the patient has at least one eye with a total
corneal fluorescein staining score at least equal or higher than 11
(NEI scale). [0114] 1.50 The composition for use of any of the
preceding items, wherein the patient has at least one eye with a
central corneal fluorescein staining value in the range of 1 to 3
(NEI scale). [0115] 1.51 The composition for use of any of the
preceding items, wherein the patient has at least one eye with a
total lissamine green conjunctival staining score in the range of 2
to 6. [0116] 1.52 The composition for use of any of the preceding
items, wherein the patient has at least one eye with an
unanesthetized Schirmer's test score in the range of 4 to 6 mm.
[0117] 1.53 The composition for use of any of the preceding items,
wherein the central corneal fluorescein staining value is about 3
(NEI scale). [0118] 1.54 The composition for use of any of the
preceding items, wherein the lissamine green conjunctival staining
score is in the range of 3 to 5. [0119] 1.55 The composition for
use of any of the preceding items, wherein the unanesthetized
Schirmer's test score is about 5 mm. [0120] 1.56 An ophthalmic
composition comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane for use in a method of treating
keratoconjunctivitis sicca (dry eye disease), wherein the method
comprises a step of topically administering the composition to an
eye of a patient, wherein the patient has at least one eye with a
total corneal fluorescein staining score at least equal or higher
than 11 (NEI scale). [0121] 1.57 An ophthalmic composition
comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane for use in a method of treating
keratoconjunctivitis sicca (dry eye disease), wherein the method
comprises a step of topically administering the composition to an
eye of a patient, wherein the patient has a total ocular surface
disease index (OSDI) score of equal or greater than 45, and wherein
the patient has at least one eye with a total corneal fluorescein
staining score at least equal or higher than 11 (NEI scale). [0122]
1.58 An ophthalmic composition comprising 0.1% (w/v) cyclosporine
dissolved in 1-(perfluorobutyl)pentane for use in a method of
treating keratoconjunctivitis sicca (dry eye disease), wherein the
method comprises a step of topically administering the composition
to an eye of a patient, wherein the patient has a total ocular
surface disease index (OSDI) score of equal or greater than 45, and
wherein the patient has at least one eye with:
[0123] a total corneal fluorescein staining score at least equal or
higher than 11 (NEI scale); and [0124] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale).
[0125] 1.59 An ophthalmic composition comprising 0.1% (w/v)
cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a
method of treating keratoconjunctivitis sicca (dry eye disease),
wherein the method comprises a step of topically administering the
composition to an eye of a patient, wherein the patient has a total
ocular surface disease index (OSDI) score of equal or greater than
45, and wherein the patient has at least one eye with: [0126] a
total corneal fluorescein staining score at least equal or higher
than 11 (NEI scale); [0127] a central corneal fluorescein staining
value in the range of 1 to 3 (NEI scale); and [0128] a total
lissamine green conjunctival staining score in the range of 2 to 6.
[0129] 1.60 An ophthalmic composition comprising 0.1% (w/v)
cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in a
method of treating keratoconjunctivitis sicca (dry eye disease),
wherein the method comprises a step of topically administering the
composition to an eye of a patient, wherein the patient has a total
ocular surface disease index (OSDI) score of equal or greater than
45, and wherein the patient has at least one eye with: [0130] a
total corneal fluorescein staining score at least equal or higher
than 11 (NEI scale); [0131] a central corneal fluorescein staining
value in the range of 1 to 3 (NEI scale); [0132] a total lissamine
green conjunctival staining score in the range of 2 to 6; and
[0133] an unanesthetized Schirmer's test score in the range of 4 to
6 mm. [0134] 1.61 The composition for use in any one of items 1.58
to 1.60, wherein the central corneal fluorescein staining value is
about 3 (NEI scale). [0135] 1.62 The composition for use in any one
of items 1.59 to 1.61, wherein the lissamine green conjunctival
staining score is in the range of 3 to 5. [0136] 1.63 The
composition for use in any one of items 1.60 to 1.62, wherein the
unanesthetized Schirmer's test score is about 5 mm. [0137] 1.64 The
composition for use in any one of items 1.57 to 1.63, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 55. [0138] 1.65 The composition for use in
any one of items 1.49 to 1.64, wherein the patient has the total
corneal flueorescein staining score, the central corneal
fluorescein staining value, the lissamine green conjunctival
staining score, and/or the unanesthetized Schirmer's test score
with the specified values in both eyes.
[0139] In a second aspect the present disclosure may relate to a
method of treatment according to the following: [0140] 2.1 A method
of treating keratoconjunctivitis sicca (dry eye disease) comprising
a step of topically administering an ophthalmic composition
comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane to an eye of a patient, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 45. [0141] 2.2 Method 2.1, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 55. [0142] 2.3 Any preceding method, wherein
the composition comprises up to about 1.0% (w/w) ethanol. [0143]
2.4 Any preceding method, wherein the composition consists of about
0.1% (w/v) cyclosporine, F4H5 and up to about 1.0% (w/w) ethanol.
[0144] 2.5 Any preceding method, wherein the ophthalmic composition
is administered to the surface of the cornea and/or conjunctiva in
the form of a liquid drop. [0145] 2.6 Any preceding method, wherein
the composition is administered as a single drop having a volume of
about 8 to 11 .mu.L, preferably of about 8 to 10 .mu.L. [0146] 2.7
Any preceding method, wherein the composition is administered in a
dose of a single drop per eye one time per day in volume of 8-10
.mu.L. [0147] 2.8 Any preceding method, wherein the composition is
administered as a single drop having a volume of about 10 .mu.l.
[0148] 2.9 Any preceding method, wherein the composition is
administered twice per day per eye. [0149] 2.10 Any preceding
method, wherein the composition is administered in a dose of a
single drop per eye twice per day in net volume of about 16-20
.mu.L. [0150] 2.11 Any preceding method, wherein the dry eye
disease is aqueous-deficient dry eye disease. [0151] 2.12 Any
preceding method, wherein the dry eye disease is evaporative dry
eye disease. [0152] 2.13 Any preceding method, wherein the patient
is non-responsive, or insufficiently responsive to treatment with
aqueous ophthalmic eye drop compositions (e.g. aqueous cyclosporin
emulsion eye drops). [0153] 2.14 Any preceding method, wherein the
time interval between topical administration of the composition to
the eye or eye surface of a first dose and a second dose is at
least 4 hours, or at least 6 hours, or at least 12 hours. [0154]
2.15 Any preceding method, wherein the duration of the treatment is
for at at least 2 weeks, or at least 4 weeks, or at least 6 weeks,
or at least 8 weeks, or at least 12 weeks. [0155] 2.16 Any
preceding method, wherein the patient is a human patient. [0156]
2.17 Any preceding method, wherein the patient is a female patient.
[0157] 2.18 Any preceding method, wherein the patient is a male
patient. [0158] 2.19 Any preceding method, wherein the patient is
aged 20-80 years old at the time of treatment, e.g., 20-50 years
old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or
30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70
years old, or 50-80 years old, or 50-70 years old. [0159] 2.20 Any
preceding method, wherein the patient suffers from a co-morbidity,
for example, conjunctivitis, stye, chalazion, blepharitis,
ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate
keratopathy, or ocular allergies, or any combination thereof.
[0160] 2.21 Any preceding method, wherein the patient suffers from
keratoconjunctivitis sicca which is caused by treatment of a
co-morbidity, for example, treatment with any one or more of:
isotretinoin, sedatives, diuretics, tricyclic antidepressants,
antihypertensives, anticholinergics, oral contraceptives,
antihistamine, nasal decongestants, beta-adrenergic antagonists,
phenothiazines, atropine opiates (e.g., morphine), optionally
wherein any such treatment is concurrent or previous, and further
optionally, wherein any such treatment is systemic (e.g., oral or
parenteral). [0161] 2.22 Any preceding method, wherein the patient
suffers from keratoconjunctivitis sicca which is caused by ocular
surgical intervention, for example, corneal surgery, refractive
surgery, LASIK surgery, cataract surgery, optionally wherein any
such ocular surgery is concurrent or previous. [0162] 2.23 Any
preceding method, wherein the patient is concomitantly under
treatment with another topical ophthalmic medication, for example,
an antibiotic, antifungal, corticosteroid, another
immunosuppressant, sympathomimetic, anesthetic, antihistamine, or
any combination thereof. [0163] 2.24 Any preceding method, wherein
the patient is a contact lens wearer. [0164] 2.25 Any preceding
method, wherein the patient was unresponsive or insufficiently
response to previous treatment for keratoconjunctivitis sicca (dry
eye disease). [0165] 2.26 Method 2.25, wherein said previous
treatment comprise one or more of the following treatment methods:
topical aqueous immunosuppressant administration, (e.g., topical
aqueous ciclosporin), topical corticosteroid administration, or
topical aqueous artificial tears administration. [0166] 2.27 Any
preceding method, wherein the patient has at least one eye with a
total corneal fluorescein staining score of at least equal or
higher than 10. [0167] 2.28 Any preceding method, wherein the
patient has at least one eye with any one or combination of
criteria (e.g. signs of dry eye disease) selected from the group
consisting of: [0168] i. A total lissamine green conjunctival score
(sum of temporal and nasal regions) of 2 according to the Oxford
scale; [0169] ii. a total corneal fluorescein staining (NEI scale)
of 10 (i.e. sum of inferior, superior, central, nasal and temporal
regions); [0170] iii. an unanesthetized Schirmer's Test score
between 1 mm and 10 mm. [0171] 2.29 Method 2.28, wherein the
patient has at least one eye (i.e. the same eye) which meets
criteria (i), (ii) and (iii). [0172] 2.30 Any preceding method,
wherein the patient has at least one eye, or both eyes with any one
or combination of: [0173] i. a central corneal fluorescein staining
(NEI scale) score of 2 or higher, [0174] ii. an inferior corneal
fluorescein staining (NEI scale) score of 2 or higher, [0175] iii.
a total corneal fluorescein staining (NEI scale) score of 11 or
higher. [0176] 2.31 Any preceding method, wherein the patient has a
history of keratoconjunctivitis sicca (dry eye disease) in one or
both eyes for at least six months. [0177] 2.32 Any preceding
method, wherein the composition is effective in reducing one or
more signs and/or symptoms of keratoconjunctivitis sicca (dry eye
disease), preferably wherein the one or more signs and/or symptoms
is selected from ocular surface damage. [0178] 2.33 Any preceding
method, wherein the composition is effective in reducing the one or
more signs and/or symptoms of keratoconjunctivitis sicca (dry eye
disease) within 2 weeks, within 4 weeks, or within 8 weeks after
first administration of the composition/commencement of treatment.
[0179] 2.34 Any preceding method, wherein the composition is
effective in reducing ocular surface damage. [0180] 2.35 Method
2.32 to 2.34, wherein the ocular surface damage is selected from
the group consisting of: [0181] i. surface damage of the total
corneal region; [0182] ii. surface damage of the central corneal
region; [0183] iii. surface damage of the nasal corneal region;
[0184] iv. surface damage of the temporal corneal region; [0185] v.
surface damage of the inferior corneal region; and [0186] vi.
combinations thereof. [0187] 2.36 Method 2.35, wherein the ocular
surface damage is selected from ocular surface damage in the
central corneal region and ocular surface damage of the inferior
corneal region. [0188] 2.37 Method 2.32 to 2.36 wherein the
reduction of ocular surface damage is determined by corneal
fluorescein staining (NEI scale). [0189] 2.38 Method 2.37, wherein
the corneal fluorescein staining method is selected from the group
consisting of: [0190] iv. total corneal fluorescein staining;
[0191] v. central corneal fluorescein staining; [0192] vi. nasal
corneal fluorescein staining; [0193] vii. temporal fluorescein
staining; [0194] viii. inferior corneal fluorescein staining; and
[0195] ix. any combination thereof. [0196] 2.39 Method 2.32 to
2.38, wherein the treatment is effective in reducing the total
corneal fluorescein staining score (sum of inferior, superior,
central, nasal, and temporal staining scores; NEI scale) by an
integer of at least 2, or by at least 3 points, optionally within a
treatment period of at least 8 weeks, or at least 12 weeks. [0197]
2.40 Any preceding method, wherein the composition is effective in
treating one or more ocular symptoms of keratoconjunctivitis sicca
(dry eye disease) selected from (x) dryness, (xi) sticky feeling,
(xii) burning/stinging, (xiii) foreign body sensation, (xiv)
itching, (xv) blurred vision, (xvi) sensitivity to light, (xvii)
pain, (xviii) and any combination thereof. [0198] 2.41 Any
preceding method, wherein the composition is effective in reducing
the (xix) frequency of dryness, (xx) awareness of symptoms and
(xxi) the severity of dryness and (xxi) any combination thereof.
[0199] 2.42 Method 2.40 to 2.41, wherein the composition is
effective in reducing the severity of dryness or the frequency of
dryness or the combination thereof. [0200] 2.43 Any preceding
method, wherein the method of treatment comprises the reduction of
ocular surface damage, e.g. ocular surface damage of the cornea, or
ocular surface damage selected from: i. surface damage of the total
corneal region; ii. surface damage of the central corneal region;
iii. surface damage of the nasal corneal region; iv. surface damage
of the temporal corneal region; v. surface damage of the inferior
corneal region; and vi. combinations thereof. [0201] 2.44 Method
2.43, wherein the ocular surface damage is selected from ocular
surface damage in the central corneal region and ocular surface
damage of the inferior corneal region. [0202] 2.45 Method 2.43 to
2.44 wherein the ocular surface damage is determined by corneal
fluorescein staining (NEI scale). [0203] 2.46 Any preceding method,
wherein the patient has at least one eye with any one or
combination of criteria selected from the group consisting of:
[0204] a total corneal fluorescein staining value in the range of
10 to 15, preferably 10 to 13 (NEI scale); [0205] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale);
[0206] preferably 2 to 3 (NEI scale); [0207] a total lissamine
green conjunctival staining score in the range of 2 to 6,
preferably 3 to 5; [0208] an unanesthetized Schirmer's test score
in the range of 2 to 8 mm. [0209] 2.47 Any preceding method, in
which the patient does not suffer from blepharitis and/or meibomian
gland dysfunction. [0210] 2.48 Any preceding method, wherein the
patient has an unanesthetized Schirmer's Test score in the range of
3 to 7 mm, preferably in the range of 4 to 6 mm, more preferably of
about 5 mm. [0211] 2.49 Any preceding method, wherein the patient
has at least one eye with a total corneal fluorescein staining
score at least equal or higher than 11 (NEI scale). [0212] 2.50 Any
preceding method, wherein the patient has at least one eye with a
central corneal fluorescein staining value in the range of 1 to 3
(NEI scale). [0213] 2.51 Any preceding method, wherein the patient
has at least one eye with a total lissamine green conjunctival
staining score in the range of 2 to 6. [0214] 2.52 Any preceding
method, wherein the patient has at least one eye with an
unanesthetized Schirmer's test score in the range of 4 to 6 mm.
[0215] 2.53 Any preceding method, wherein the central corneal
fluorescein staining value is about 3 (NEI scale). [0216] 2.54 Any
preceding method, wherein the lissamine green conjunctival staining
score is in the range of 3 to 5. [0217] 2.55 Any preceding method,
wherein the unanesthetized Schirmer's test score is about 5 mm.
[0218] 2.56 A method of treating keratoconjunctivitis sicca (dry
eye disease) comprising a step of topically administering an
ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane to an eye of a patient, wherein the
patient has at least one eye with a total corneal fluorescein
staining score at least equal or higher than 11 (NEI scale). [0219]
2.57 A method of treating keratoconjunctivitis sicca (dry eye
disease) comprising a step of topically administering an ophthalmic
composition comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane to an eye of a patient, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 45, and wherein the patient has at least one
eye with a total corneal fluorescein staining score at least equal
or higher than 11 (NEI scale). [0220] 2.58 A method of treating
keratoconjunctivitis sicca (dry eye disease) comprising a step of
topically administering an ophthalmic composition comprising 0.1%
(w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane to an eye
of a patient, wherein the patient has a total ocular surface
disease index (OSDI) score of equal or greater than 45, and wherein
the patient has at least one eye with: [0221] a total corneal
fluorescein staining score at least equal or higher than 11 (NEI
scale); and [0222] a central corneal fluorescein staining value in
the range of 1 to 3 (NEI scale). [0223] 2.59 A method of treating
keratoconjunctivitis sicca (dry eye disease) comprising a step of
topically administering an ophthalmic composition comprising 0.1%
(w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane to an eye
of a patient, wherein the patient has a total ocular surface
disease index (OSDI) score of equal or greater than 45, and wherein
the patient has at least one eye with: [0224] a total corneal
fluorescein staining score at least equal or higher than 11 (NEI
scale); [0225] a central corneal fluorescein staining value in the
range of 1 to 3 (NEI scale); and [0226] a total lissamine green
conjunctival staining score in the range of 2 to 6. [0227] 2.60 A
method of treating keratoconjunctivitis sicca (dry eye disease)
comprising a step of topically administering an ophthalmic
composition comprising 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane to an eye of a patient, wherein the
patient has a total ocular surface disease index (OSDI) score of
equal or greater than 45, and wherein the patient has at least one
eye with: [0228] a total corneal fluorescein staining score at
least equal or higher than 11 (NEI scale); [0229] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale);
[0230] a total lissamine green conjunctival staining score in the
range of 2 to 6; and [0231] an unanesthetized Schirmer's test score
in the range of 4 to 6 mm. [0232] 2.61 Method 2.58 to 2.60, wherein
the central corneal fluorescein staining value is about 3 (NEI
scale). [0233] 2.62 Method 2.59 to 2.61, wherein the lissamine
green conjunctival staining score is in the range of 3 to 5.
[0234] 2.63 Method 2.60 to 2.62, wherein the unanesthetized
Schirmer's test score is about 5 mm. [0235] 2.64 Method 2.57 to
2.63, wherein the patient has a total ocular surface disease index
(OSDI) score of equal or greater than 55. [0236] 2.65 Method 2.49
to 2.64, wherein the patient has the total corneal flueorescein
staining score, the central corneal fluorescein staining value, the
lissamine green conjunctival staining score, and/or the
unanesthetized Schirmer's test score with the specified values in
both eyes.
[0237] In a third aspect, the present invention provides for the
following items: [0238] 3.1 An ophthalmic composition comprising
0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl) pentane for
use in: [0239] a) a method of treating and/or ameliorating the
symptoms associated with keratoconjunctivitis sicca (dry eyes),
wherein the symptoms are dryness (severity of dryness) and blurred
vision; [0240] and/or [0241] b) a method of treating and/or
ameliorating the awareness of symptoms of dry eyes and the
frequency of dryness, preferably wherein the symptoms of dry eyes
are selected from dryness, sticky feeling, burning/stinging,
foreign body sensation, itching, blurred vision, sensitivity to
light, and pain in the eyes of a patient. [0242] 3.2 The
composition for use of 3.1, wherein the composition is topically
administered to the eye of a patient. [0243] 3.3 The composition
for use according to 3.1 or 3.2, wherein the dryness (severity of
dryness), the blurred vision, the frequency of dryness and the
awareness of symptoms of dry eyes are determined on a visual analog
scale (VAS) on a scale of 0% to 100%, wherein for frequency of
dryness and awareness of dry eyes symptoms the scale of 0% to 100%
is the percentage of time dryness and dry eyes symptoms are
experienced by a patient and wherein for dryness and blurred vision
the scale of 0% to 100% is the percentage level of discomfort
experienced by a patient. [0244] 3.4 The composition for use of any
one of the preceding items, wherein the composition comprises up to
about 1.0% (w/w) ethanol. [0245] 3.5 The composition for use of any
one of the preceding items, wherein the composition consists of
about 0.1% (w/v) cyclosporine, 1-perfluorobutylpentane (F4H5) and
up to about 1.0% (w/w) ethanol. [0246] 3.6 The composition for use
of any of the preceding items, wherein the ophthalmic composition
is administered to the surface of the cornea and/or conjunctiva in
the form of a liquid drop. [0247] 3.7 The composition for use in
any of the preceding items, wherein the composition is administered
as a single drop having a volume of about 8 to 11 .mu.L, preferably
of about 8 to 10 .mu.L. [0248] 3.8 The composition for use of any
of the preceding items, wherein the composition is administered in
a dose of a single drop per eye in volume of about 8 to 10 .mu.L.
[0249] 3.9 The composition for use according to any one of the
preceding claims, wherein the composition is administered as a
single drop having a volume of about 10 .mu.l. [0250] 3.10 The
ophthalmic composition for use of any one of the preceding items,
wherein the composition is administered twice per day per eye.
[0251] 3.11 The composition for use in any of the preceding items,
wherein the composition is administered in a dose of a single drop
per eye twice per day in net volume of about 16-20 .mu.L. [0252]
3.12 The composition for use according to any one of the preceding
items, wherein the dry eye disease is aqueous-deficient dry eye
disease. [0253] 3.13 The composition for use according to any of
the preceding items, wherein the dry eye disease is evaporative dry
eye disease. [0254] 3.14 The composition for use in according to
any of the preceding items, wherein the patient is non-responsive,
or insufficiently responsive, to treatment with aqueous ophthalmic
eye drop compositions. [0255] 3.15 The composition for use of any
of the preceding items, wherein the time interval between topical
administration of the composition to the eye or eye surface of a
first dose and a second dose is at least 4 hours, or at least 6
hours, or at least 12 hours. [0256] 3.16 The composition for use of
any of the preceding items, wherein the duration of the treatment
is for at least 2 weeks, or at least 4 weeks, or at least 6 weeks,
or at least 8 weeks, or at least 12 weeks. [0257] 3.17 The
composition for use of any of the preceding items wherein the
patient is a human patient. [0258] 3.18 The composition for use of
any of the preceding items, wherein the patient is a female
patient. [0259] 3.19 The composition for use of any of the
preceding items, wherein the patient is a male patient. [0260] 3.20
The composition for use of any of the preceding items, wherein the
patient is aged 20-80 years old at the time of treatment, e.g.,
20-50 years old, or 20-70 years old, or 30-80 years old, or 30-50
years old, or 30-70 years old, or 40-80 years old, or 40-60 years
old, or 40-70 years old, or 50-80 years old, or 50-70 years old.
[0261] 3.21 The composition for use of any of the preceding items,
wherein the patient suffers from a co-morbidity, for example,
conjunctivitis, stye, chalazion, blepharitis, ectropion, eyelid
laxity, eyelid edema, eyelid dermatitis, punctate keratopathy, or
ocular allergies, or any combination thereof. [0262] 3.22 The
composition for use of any of the preceding items, wherein the
patient suffers from keratoconjunctivitis sicca which is caused by
treatment of a co-morbidity, for example, treatment with any one or
more of: isotretinoin, sedatives, diuretics, tricyclic
antidepressants, antihypertensives, anticholinergics, oral
contraceptives, antihistamine, nasal decongestants, beta-adrenergic
antagonists, phenothiazines, atropine opiates (e.g., morphine),
optionally wherein any such treatment is concurrent or previous,
and further optionally, wherein any such treatment is systemic
(e.g., oral or parenteral). [0263] 3.23 The composition for use of
any of the preceding items, wherein the patient suffers from
keratoconjunctivitis sicca which is caused by ocular surgical
intervention, for example, corneal surgery, refractive surgery,
LASIK surgery, cataract surgery, optionally wherein any such ocular
surgery is concurrent or previous. [0264] 3.24 The composition for
use of any of the preceding items, wherein the patient is
concomitantly under treatment with another topical ophthalmic
medication, for example, an antibiotic, antifungal, corticosteroid,
another immunosuppressant, sympathomimetic, anesthetic,
antihistamine, or any combination thereof. [0265] 3.25 The
composition for use of any of the preceding items, wherein the
patient is a contact lens wearer. [0266] 3.26 The composition for
use of any of the preceding items, wherein the patient was
unresponsive or insufficiently responsive to previous treatment for
keratoconjunctivitis sicca (dry eye disease). [0267] 3.27 The
composition for use in 3.26, wherein said previous treatment
comprise one or more of the following treatment methods: topical
aqueous immunosuppressant administration (e.g., topical aqueous
ciclosporin), topical corticosteroid administration, or topical
aqueous artificial tears administration. [0268] 3.28 The
composition for use of any of the preceding items, wherein the
patient has at least one eye with any one, or combination of
criteria (e.g. signs of dry eye disease) selected from the group
consisting of: [0269] i. A total lissamine green conjunctival score
(sum of temporal and nasal regions) of 2 according to the Oxford
scale; [0270] ii. a total corneal fluorescein staining (NEI scale)
of 10 (i.e. sum of inferior, superior, central, nasal and temporal
regions); and [0271] iii. an unanesthetized Schirmer's Test score
between 1 mm and 10 mm; [0272] and/or [0273] wherein the patient
has a total ocular surface disease index score (OSDI) of equal or
greater than 20. [0274] 3.29 The composition for use according to
any of the preceding items, wherein the patient has a total ocular
surface disease index score (OSDI) of equal or greater than 45.
[0275] 3.30 The composition for use according to any of the
preceding items, wherein the patient has a total ocular surface
disease index score (OSDI) of equal or greater than 55. [0276] 3.31
The composition for use according to item 3.28 to 3.30, wherein the
patient has at least one eye (i.e. the same eye) which meets all of
criteria (i), (ii), and (iii). [0277] 3.32 The composition for use
of any of the preceding items, wherein the patient has a history of
keratoconjunctivitis sicca (dry eye disease) in one or both eyes
for at least six months. [0278] 3.33 The composition for use of any
of the preceding items, wherein the composition is effective in
reducing one or more signs and/or symptoms of keratoconjunctivitis
sicca (dry eye disease), preferably wherein the signs and/or
symptoms is selected from ocular surface damage. [0279] 3.34 The
composition for use of any of the preceding items, wherein the
composition is effective in reducing one or more signs and/or
symptoms of keratoconjunctivitis sicca (dry eye disease) within 2
weeks, or within 4 weeks, or within 8 weeks after first
administration of the composition. [0280] 3.35 The composition for
use in in any of the preceding items, wherein the composition is
effective in reducing ocular surface damage. [0281] 3.36 The
composition for use according to item 3.35, wherein the ocular
surface damage is selected from the group consisting of: [0282] i.
surface damage of the total corneal region; [0283] ii. surface
damage of the central corneal region; [0284] iii. surface damage of
the nasal corneal region; [0285] iv. surface damage of the temporal
corneal region; [0286] v. surface damage of the inferior corneal
region; and [0287] vi. combinations thereof. [0288] 3.37 The
composition for use of item 3.36, wherein the ocular surface damage
is selected from ocular surface damage in the central corneal
region and ocular surface damage of the inferior corneal region.
[0289] 3.38 The composition for use of item 3.35 to 3.37 wherein
the reduction of ocular surface damage is determined by corneal
fluorescein staining (NEI scale). [0290] 3.39 The composition for
use in item 3.38, wherein the corneal fluorescein staining method
is selected from the group consisting of: [0291] iv. total corneal
fluorescein staining; [0292] v. central corneal fluorescein
staining; [0293] vi. nasal corneal fluorescein staining; [0294]
vii. temporal fluorescein staining; [0295] viii. inferior corneal
fluorescein staining; and [0296] ix. any combination thereof.
[0297] 3.40 The composition for use of any of the preceding items,
wherein the composition is effective in reducing the frequency of
dryness and/or the awareness of dry eye symptoms and/or the
severity of dryness and any combination thereof. [0298] 3.41 The
composition for use of item 3.40, wherein the composition is
effective in reducing the frequency of dryness and/or the awareness
of dry eye symptoms and/or the severity of dryness, or any
combination thereof, within 2 weeks after start of treatment, or
within 4 weeks after start of treatment. [0299] 3.42 The
composition for use of item 3.40 or 3.41 wherein the composition is
effective in reducing the frequency of dryness and/or the severity
of dryness by at least 25%, preferably by at least 30% after two
weeks or after four weeks or after 8 weeks or after 12 weeks of
treatment. [0300] 3.43 The composition for use of item 3.40 to
3.42, wherein the composition is effective in reducing the severity
of dryness and/or the frequency of dryness by at least 25% in more
than at least 20% of patients undergoing treatment after two weeks
of treatment; or in more than 30% of patients undergoing treatment
after four weeks of treatment; or in more than at least 35% of
patients under going treatment after eight weeks of treatment.
[0301] 3.44 The composition for use of items 3.40 to 3.43, wherein
the effectiveness of the composition for use is determined by
visual analog scale (VAS) testing on a scale of 0 to 100%, wherein
frequency of dryness and awareness of dry eye symptoms are measured
on a scale of 0 to 100% as the percentage of time said symptom(s)
is experienced by a patient and wherein the severity of dryness is
measured on a scale of 0 to 100% as the percentage level of
discomfort experienced by the patient. [0302] 3.45 The composition
for use of any preceding item, wherein the method of treatment
comprises reducing ocular surface damage, e.g. ocular surface
damage of the cornea, or ocular surface damage selected from i.
surface damage of the total corneal region; ii. surface damage of
the central corneal region; iii. surface damage of the nasal
corneal region; iv. surface damage of the temporal corneal region;
v. surface damage of the inferior corneal region; and vi.
combinations thereof. [0303] 3.46 The composition for use of item
3.45, wherein the ocular surface damage is selected from ocular
surface damage in the central corneal region and ocular surface
damage of the inferior corneal region. [0304] 3.47 The composition
for use of item 3.45 to 3.46 wherein the ocular surface damage is
determined by corneal fluorescein staining (NEI scale). [0305] 3.48
The composition for use of any of the preceding items, wherein
patient has at least one eye with any one or combination of
criteria selected from the group consisting of: [0306] a total
corneal fluorescein staining value in the range of 10 to 15,
preferably 10 to 13 (NEI scale); [0307] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale);
preferably 2 to 3 (NEI scale); [0308] a total lissamine green
conjunctival staining score in the range of 2 to 6, preferably 3 to
5; [0309] an unanesthetized Schirmer's test score in the range of 2
to 8 mm; [0310] a total OSDI score in the range of 25 to 64,
preferably 30 to 64. [0311] 3.49 The composition for use of any of
the preceding items, wherein the patient has an unanesthetized
Schirmer's Test score in the range of 3 to 7 mm, preferably in the
range of 4 to 6 mm, more preferably of about 5 mm. [0312] 3.50 The
composition for use of any of the preceding items, wherein the
composition is effective in reducing in a patient the total corneal
fluorescein staining score (sum of inferior, superior, central,
nasal, and temporal staining scores; NEI scale), by at least 3
grades after 4 weeks of treatment, preferably in at least 50% of
the patients undergoing treatment. [0313] 3.51 The composition for
use of any preceding items, wherein the composition is effective in
reducing the central corneal fluoresceing staining score in a
patient by at least 1 grade after four weeks of treatment,
preferably in at least 50% of the patients undergoing treatment.
[0314] 3.52 The composition for use of any preceding items, wherein
the composition is effective in reducing the conjunctival lissamine
green staining (Oxford scale) in a patient by at least 2 grades
after four weeks or after twelve weeks of treatment, preferably in
at least 30% of the patients undergoing treatment after four weeks
of treatment or preferably in at least 50% of the patients after
twelve weeks of treatment. [0315] 3.53 The composition for use of
any of the preceding items, wherein the patient does not suffer
from meibomian gland dysfunction and/or blepharitis. [0316] 3.54
The composition for use of any of the preceding items, wherein the
patient has at least one eye with a total corneal fluorescein
staining score at least equal or higher than 11 (NEI scale).
[0317] 3.55 The composition for use of any of the preceding items,
wherein the patient has at least one eye with a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale).
[0318] 3.56 The composition for use of any of the preceding items,
wherein the patient has at least one eye with a total lissamine
green conjunctival staining score in the range of 2 to 6. [0319]
3.57 The composition for use of any of the preceding items, wherein
the patient has at least one eye with an unanesthetized Schirmer's
test score in the range of 4 to 6 mm. [0320] 3.58 The composition
for use of any of the preceding items, wherein the central corneal
fluorescein staining value is about 3 (NEI scale). [0321] 3.59 The
composition for use of any of the preceding items, wherein the
lissamine green conjunctival staining score is in the range of 3 to
5. [0322] 3.60 The composition for use of any of the preceding
items, wherein the unanesthetized Schirmer's test score is about 5
mm. [0323] 3.61 An ophthalmic composition comprising 0.1% (w/v)
cyclosporine dissolved in 1-(perfluorobutyl)pentane for use in:
[0324] a) a method of treating and/or ameliorating the symptoms
associated with keratoconjunctivitis sicca (dry eyes), wherein the
symptoms are dryness (severity of dryness) and blurred vision;
[0325] and/or [0326] b) a method of treating and/or ameliorating
the awareness of symptoms of dry eyes and the frequency of dryness,
preferably wherein the symptoms of dry eyes are selected from
dryness, sticky feeling, burning/stinging, foreign body sensation,
itching, blurred vision, sensitivity to light, and pain in the eyes
of a patient; wherein the composition is topically administered to
the eye of a patient, and wherein the patient has at least one eye
with a total corneal fluorescein staining score at least equal or
higher than 11 (NEI scale). [0327] 3.62 The composition for use of
item 3.61, wherein the patient has at least one eye with a central
corneal fluorescein staining value in the range of 1 to 3 (NEI
scale). [0328] 3.63 The composition for use of item 3.61 or 3.62,
wherein the patient has at least one eye with a total lissamine
green conjunctival staining score in the range of 2 to 6. [0329]
3.64 The composition for use of any one of items 3.61 to 3.63,
wherein the patient has at least one eye with an unanesthetized
Schirmer's test score in the range of 4 to 6 mm. [0330] 3.65 The
composition for use of any one of items 3.62 to 3.64, wherein the
central corneal fluorescein staining value is about 3 (NEI scale).
[0331] 3.66 The composition for use of any one of items 3.63 to
3.65, wherein the lissamine green conjunctival staining score is in
the range of 3 to 5. [0332] 3.67 The composition for use of any one
of items 3.64 to 3.66, wherein the unanesthetized Schirmer's test
score is about 5 mm. [0333] 3.68 The composition for use of any one
of items 3.61 to 3.67, wherein the patient has a total ocular
surface disease index score (OSDI) of equal or greater than 45.
[0334] 3.69 The composition for use of any one of items 3.61 to
3.68, wherein the patient has a total ocular surface disease index
score (OSDI) of equal or greater than 55. [0335] 3.70 The
composition for use in any one of items 3.54 to 3.69, wherein the
patient has the total corneal flueorescein staining score, the
central corneal fluorescein staining value, the lissamine green
conjunctival staining score, and/or the unanesthetized Schirmer's
test score with the specified values in both eyes.
[0336] In a fourth aspect, the present invention provides for the
following method: [0337] 4.1 A method of treating and/or
ameliorating the symptoms associated with keratoconjunctivitis
sicca (dry eyes) wherein the symptoms are dryness (severity of
dryness) and blurred vision, and wherein the method comprises
administering an ophthalmic composition comprising 0.1% (w/v)
cyclosporine dissolved in 1-(perfluorobutyl)pentane to an eye of a
patient. [0338] 4.2 Method 4.1 and/or a method of treating and/or
ameliorating the awareness of symptoms of dry eyes and the
frequency of dryness, preferably wherein the symptoms of dry eye
are selected from dryness, sticky feeling, burning/stinging,
foreign body sensation, itching, blurred vision, sensitivity to
light, and pain, wherein said method comprises administering an
ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane to an eye of a patient. [0339] 4.3
Method 4.1 or 4.2, wherein the composition is topically
administered to the eye of a patient. [0340] 4.4 Method 4.1 to 4.3,
wherein the dryness (severity of dryness), the blurred vision, the
frequency of dryness and the awareness of symptoms of dry eyes are
determined on a visual analog scale (VAS) on a scale of 0% to 100%,
wherein for frequency of dryness and awareness of dry eyes symptoms
the scale of 0% to 100% is the percentage of time dryness and dry
eyes symptoms are experienced by a patient and wherein for dryness
and blurred vision the scale of 0% to 100% is the percentage level
of discomfort experienced by a patient. [0341] 4.5 Any preceding
method, wherein the composition comprises up to about 1.0% (w/w)
ethanol. [0342] 4.6 Any preceding method, wherein the composition
consists of about 0.1% (w/v) cyclosporine,
1-(perfluorobutyl)pentane (F4H5) and up to about 1.0% (w/w)
ethanol. [0343] 4.7 Any preceding method, wherein the ophthalmic
composition is administered to the surface of the cornea and/or
conjunctiva in the form of a liquid drop. [0344] 4.8 Any preceding
method, wherein the composition is administered as a single drop
having a volume of about 8 to 11 .mu.L, preferably of about 8 to 10
.mu.L. [0345] 4.9 Any preceding method, wherein the composition is
administered in a dose of a single drop per eye in volume of about
8 to 10 .mu.L. [0346] 4.10 Any preceding method, wherein the
composition is administered as a single drop having a volume of
about 10 .mu.l. [0347] 4.11 Any preceding method, wherein the
composition is administered twice per day per eye. [0348] 4.12 Any
preceding method, wherein the composition is administered in a dose
of a single drop per eye twice per day in net volume of about 16-20
.mu.L. [0349] 4.13 Any preceding method, wherein the dry eye
disease is aqueous-deficient dry eye disease. [0350] 4.14 Any
preceding method, wherein the dry eye disease is evaporative dry
eye disease. [0351] 4.15 Any preceding method, wherein the patient
is non-responsive, or insufficiently responsive, to treatment with
aqueous ophthalmic eye drop compositions. [0352] 4.16 Any preceding
method, wherein the time interval between topical administration of
the composition to the eye or eye surface of a first dose and a
second dose is at least 4 hours, or at least 6 hours, or at least
12 hours. [0353] 4.17 Any preceding method, wherein the duration of
the treatment is for at least 2 weeks, or at least 4 weeks, or at
least 6 weeks, or at least 8 weeks, or at least 12 weeks. [0354]
4.18 Any preceding method, wherein the patient is a human patient.
[0355] 4.19 Any preceding method, wherein the patient is a female
patient. [0356] 4.20 Any preceding method, wherein the patient is a
male patient. [0357] 4.21 Any preceding method, wherein the patient
is aged 20-80 years old at the time of treatment, e.g., 20-50 years
old, or 20-70 years old, or 30-80 years old, or 30-50 years old, or
30-70 years old, or 40-80 years old, or 40-60 years old, or 40-70
years old, or 50-80 years old, or 50-70 years old. [0358] 4.22 Any
preceding method, wherein the patient suffers from a co-morbidity,
for example, conjunctivitis, stye, chalazion, blepharitis,
ectropion, eyelid laxity, eyelid edema, eyelid dermatitis, punctate
keratopathy, or ocular allergies, or any combination thereof.
[0359] 4.23 Any preceding method, wherein the patient suffers from
keratoconjunctivitis sicca which is caused by treatment of a
co-morbidity, for example, treatment with any one or more of:
isotretinoin, sedatives, diuretics, tricyclic antidepressants,
antihypertensives, anticholinergics, oral contraceptives,
antihistamine, nasal decongestants, beta-adrenergic antagonists,
phenothiazines, atropine opiates (e.g., morphine), optionally
wherein any such treatment is concurrent or previous, and further
optionally, wherein any such treatment is systemic (e.g., oral or
parenteral). [0360] 4.24 Any preceding method, wherein the patient
suffers from keratoconjunctivitis sicca which is caused by ocular
surgical intervention, for example, corneal surgery, refractive
surgery, LASIK surgery, cataract surgery, optionally wherein any
such ocular surgery is concurrent or previous. [0361] 4.25 Any
preceding method, wherein the patient is concomitantly under
treatment with another topical ophthalmic medication, for example,
an antibiotic, antifungal, corticosteroid, another
immunosuppressant, sympathomimetic, anesthetic, antihistamine, or
any combination thereof. [0362] 4.26 Any preceding method, wherein
the patient is a contact lens wearer. [0363] 4.27 Any preceding
method, wherein the patient was unresponsive or insufficiently
responsive to previous treatment for keratoconjunctivitis sicca
(dry eye disease). [0364] 4.28 Method 4.27, wherein said previous
treatment comprises one or more of the following treatment methods:
topical aqueous immunosuppressant administration (e.g., topical
aqueous ciclosporin), topical corticosteroid administration, or
topical aqueous artificial tears administration. [0365] 4.29 Any
preceding method, wherein the patient has at least one eye with any
one, or combination of criteria (e.g. signs of dry eye disease)
selected from the group consisting of: [0366] i. A total lissamine
green conjunctival score (sum of temporal and nasal regions) of
.gtoreq.2 according to the Oxford scale; [0367] ii. a total corneal
fluorescein staining (NEI scale) of .gtoreq.10 (i.e. sum of
inferior, superior, central, nasal and temporal regions); and
[0368] iii. an unanesthetized Schirmer's Test score between 1 mm
and 10 mm; [0369] and/or [0370] wherein the patient has a total
ocular surface disease index score (OSDI) of equal or greater than
20. [0371] 4.30 Any preceding method, wherein the patient has a
total ocular surface disease index score (OSDI) of equal or greater
than 45. [0372] 4.31 Any preceding method, wherein the patient has
a total ocular surface disease index score (OSDI) of equal or
greater than 55. [0373] 4.32 Method 4.29 to 4.31, wherein the
patient has at least one eye (i.e. the same eye) which meets all of
criteria (i), (ii), and (iii). [0374] 4.33 Any preceding method,
wherein the patient has a history of keratoconjunctivitis sicca
(dry eye disease) in one or both eyes for at least six months.
[0375] 4.34 Any preceding method, wherein the composition is
effective in reducing one or more signs and/or symptoms of
keratoconjunctivitis sicca (dry eye disease), preferably wherein
the signs and/or symptoms is selected from ocular surface damage
[0376] 4.35 Any preceding method, wherein the composition is
effective in reducing one or more signs and/or symptoms of
keratoconjunctivitis sicca (dry eye disease) within 2 weeks, or
within 4 weeks, or within 8 weeks after first administration of the
composition. [0377] 4.36 Any preceding method, wherein the
composition is effective in reducing ocular surface damage. [0378]
4.37 Method 4.36, wherein the ocular surface damage is selected
from the group consisting of: [0379] i. surface damage of the total
corneal region; [0380] ii. surface damage of the central corneal
region; [0381] iii. surface damage of the nasal corneal region;
[0382] iv. surface damage of the temporal corneal region; [0383] v.
surface damage of the inferior corneal region; and [0384] vi.
combinations thereof. [0385] 4.38 Method 4.37, wherein the ocular
surface damage is selected from ocular surface damage in the
central corneal region and ocular surface damage of the inferior
corneal region. [0386] 4.39 Method 4.36 to 4.38 wherein the
reduction of ocular surface damage is determined by corneal
fluorescein staining (NEI scale). [0387] 4.40 Method 4.39, wherein
the corneal fluorescein staining method is selected from the group
consisting of: [0388] iv. total corneal fluorescein staining;
[0389] v. central corneal fluorescein staining; [0390] vi. nasal
corneal fluorescein staining; [0391] vii. temporal fluorescein
staining; [0392] viii. inferior corneal fluorescein staining; and
[0393] ix. any combination thereof. [0394] 4.41 Any preceding
method, wherein the composition is effective in reducing the
frequency of dryness and/or the awareness of dry eye symptoms
and/or the severity of dryness and any combination thereof. [0395]
4.42 Method 4.41, wherein the composition is effective in reducing
the frequency of dryness and/or the awareness of dry eye symptoms
and/or the severity of dryness, or any combination thereof, within
2 weeks after start of treatment, or within 4 weeks after start of
treatment. [0396] 4.43 Method 4.41 or 4.42 wherein the composition
is effective in reducing the frequency of dryness and/or the
severity of dryness by at least 25% after two weeks or after four
weeks or after 8 weeks or after 12 weeks of treatment. [0397] 4.44
Method 4.41 to 3.43, wherein the composition is effective in
reducing the severity of dryness and/or the frequency of dryness by
at least 25% in more than 20% of patients undergoing treatment
after two weeks of treatment; or in more than 30% of patients
undergoing treatment after four weeks of treatment; or in more than
35% of patients undergoing treatment after eight weeks of
treatment. [0398] 4.45 Method 4.41 to 4.44, wherein the
effectiveness of the composition for use is determined by visual
analog scale (VAS) testing on a scale of 0 to 100%, wherein
frequency of dryness and awareness of dry eye symptoms are measured
on a scale of 0 to 100% as the percentage of time said symptom(s)
is experienced by a patient and wherein the severity of dryness is
measured on a scale of 0 to 100% as the percentage level of
discomfort experienced by the patient. [0399] 4.46 Any preceding
method, wherein the method of treatment comprises reducing ocular
surface damage, e.g. ocular surface damage of the cornea, or ocular
surface damage selected from i. surface damage of the total corneal
region; ii. surface damage of the central corneal region; iii.
surface damage of the nasal corneal region; iv. surface damage of
the temporal corneal region; v. surface damage of the inferior
corneal region; and vi. combinations thereof. [0400] 4.47 Method
4.46, wherein the ocular surface damage is selected from ocular
surface damage in the central corneal region and ocular surface
damage of the inferior corneal region. [0401] 4.48 Method 4.46 to
4.47 wherein the ocular surface damage is determined by corneal
fluorescein staining (NEI scale). [0402] 4.49 Any preceding method,
wherein the patient has at least one eye with any one or
combination of criteria selected from the group consisting of:
[0403] a total corneal fluorescein staining value in the range of
10 to 15, preferably 10 to 13 (NEI scale); [0404] a central corneal
fluorescein staining value in the range of 1 to 3 (NEI scale);
[0405] preferably 2 to 3 (NEI scale); [0406] a total lissamine
green conjunctival staining score in the range of 2 to 6,
preferably 3 to 5; [0407] an unanesthetized Schirmer's test score
in the range of 2 to 8 mm; [0408] a total OSDI score in the range
of 25 to 64, preferably 30 to 64. [0409] 4.50 Any preceding method,
in which the patient does not suffer from blepharitis and/or
meibomian gland dysfunction. [0410] 4.51 Any preceding method,
wherein the patient has an unanesthetized Schirmer's Test score in
the range of 3 to 7 mm, preferably in the range of 4 to 6 mm, more
preferably of about 5 mm. [0411] 4.52 Any preceding method, wherein
the method is effective in reducing in a patient the total corneal
fluorescein staining score (sum of inferior, superior, central,
nasal, and temporal staining scores; NEI scale), by at least 3
grades after 4 weeks of treatment, preferably in at least 50% of
the patients undergoing treatment. [0412] 4.53 Any preceding
method, wherein the method is effective in reducing the central
corneal fluoresceing staining score in a patient by at least 1
grade after four weeks of treatment, preferably in at least 50% of
the patients undergoing treatment. [0413] 4.54 Any preceding
method, wherein the method is effective in reducing the
conjunctival lissamine green staining (Oxford scale) in a patient
by at least 2 grades after four weeks or after twelve weeks of
treatment, preferably in at least 30% of the patients undergoing
treatment after four weeks of treatment or preferably in at least
50% of the patients after twelve weeks of treatment. [0414] 4.55
Any preceding method, wherein the patient has at least one eye with
a total corneal fluorescein staining score at least equal or higher
than 11 (NEI scale). [0415] 4.56 Any preceding method, wherein the
patient has at least one eye with a central corneal fluorescein
staining value in the range of 1 to 3 (NEI scale). [0416] 4.57 Any
preceding method, wherein the patient has at least one eye with a
total lissamine green conjunctival staining score in the range of 2
to 6. [0417] 4.58 Any preceding method, wherein the patient has at
least one eye with an unanesthetized Schirmer's test score in the
range of 4 to 6 mm. [0418] 4.59 Any preceding method, wherein the
central corneal fluorescein staining value is about 3 (NEI scale).
[0419] 4.60 Any preceding method, wherein the lissamine green
conjunctival staining score is in the range of 3 to 5. [0420] 4.61
Any preceding method, wherein the unanesthetized Schirmer's test
score is about 5 mm. [0421] 4.62 A method of treating and/or
ameliorating the symptoms associated with keratoconjunctivitis
sicca (dry eyes) wherein the symptoms are dryness (severity of
dryness) and blurred vision, wherein the method comprises
administering an ophthalmic composition comprising 0.1% (w/v)
cyclosporine dissolved in 1-(perfluorobutyl)pentane to an eye of a
patient, and wherein the patient has at least one eye with a total
corneal fluorescein staining score at least equal or higher than 11
(NEI scale). [0422] 4.63 Method 4.62 and/or a method of treating
and/or ameliorating the awareness of symptoms of dry eyes and the
frequency of dryness, preferably wherein the symptoms of dry eye
are selected from dryness, sticky feeling, burning/stinging,
foreign body sensation, itching, blurred vision, sensitivity to
light, and pain, wherein said method comprises administering an
ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane to an eye of a patient, and wherein
the patient has at least one eye with a total corneal fluorescein
staining score at least equal or higher than 11 (NEI scale).
[0423] 4.64 Method 4.62 or 4.63, wherein the patient has at least
one eye with a central corneal fluorescein staining value in the
range of 1 to 3 (NEI scale). [0424] 4.65 Method 4.62 to 4.64,
wherein the patient has at least one eye with a total lissamine
green conjunctival staining score in the range of 2 to 6. [0425]
4.66 Method 4.62 to 4.65, wherein the patient has at least one eye
with an unanesthetized Schirmer's test score in the range of 4 to 6
mm. [0426] 4.67 Method 4.64 to 4.66, wherein the central corneal
fluorescein staining value is about 3 (NEI scale). [0427] 4.68
Method 4.65 to 4.67, wherein the lissamine green conjunctival
staining score is in the range of 3 to 5. [0428] 4.69 Method 4.66
to 4.68, wherein the unanesthetized Schirmer's test score is about
5 mm. [0429] 4.70 Method 4.62 to 4.69, wherein the patient has a
total ocular surface disease index score (OSDI) of equal or greater
than 45. [0430] 4.71 Method 4.62 to 4.70, wherein the patient has a
total ocular surface disease index score (OSDI) of equal or greater
than 55. [0431] 4.72 Method 4.55 to 4.71, wherein the patient has
the total corneal flueorescein staining score, the central corneal
fluorescein staining value, the lissamine green conjunctival
staining score, and/or the unanesthetized Schirmer's test score
with the specified values in both eyes.
[0432] In another aspect, the present invention provides for the
following method: [0433] 5.1 A method for predicting the
improvement of visual function in a subject suffering from dry eye
disease (keratoconjunctivitis sicca) and characterized by a total
corneal fluorescein staining score in the range of 10 to 15 (NEI
scale) at baseline, wherein a decrease of the total corneal
fluorescein staining score (NEI scale) by 3 or more units is
indicative for improvement of visual function. [0434] 5.2 The
method according to item 5.1, wherein the improvement of visual
function comprises improvement in the number of words read per
minute in an international reading speed texts (IReST). [0435] 5.3
The method according to item 5.1 or 5.2, wherein the improvement of
visual function comprises improvement with regard to blurred
vision, reading, driving at night, working with a computer, working
at an automatic teller machine, reading at low contrast and reading
at low print size. [0436] 5.4 The method according to any preceding
items, wherein the subject is undergoing treatment that is
effective in reducing ocular surface damage. [0437] 5.5 The method
according to item 5.4, wherein the treatment is selected from a) an
ophthalmic composition comprising cyclosporine at a concentration
of from 0.05 to 0.1% (w/v) or b) an ophthalmic composition
comprising lifitegrast. [0438] 5.6 The method according to any
preceding items, wherein the treatment is a composition comprising
0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and
up to about 1% (w/w) ethanol. [0439] 5.7 The method according to
item 5.6, wherein the composition is administered in a dose of a
single drop per eye in volume of about 8 to 12 .mu.L. [0440] 5.8
The method according to item 5.7, wherein the composition is
administered as a single drop per eye having a volume of about
10-12 .mu.l. [0441] 5.9 The method according to any of items
5.6-5.8, wherein the composition is administered twice per day per
eye. [0442] 5.10 Any preceding method, wherein the subject has at
least one eye with a total corneal fluorescein staining score at
least equal or higher than 11 (NEI scale). [0443] 5.11 Any
preceding method, wherein the subject has at least one eye with a
central corneal fluorescein staining value in the range of 1 to 3
(NEI scale). [0444] 5.12 Any preceding method, wherein the subject
has at least one eye with a total lissamine green conjunctival
staining score in the range of 2 to 6. [0445] 5.13 Any preceding
method, wherein the subject has at least one eye with an
unanesthetized Schirmer's test score in the range of 4 to 6 mm.
[0446] 5.14 Any preceding method, wherein the central corneal
fluorescein staining value is about 3 (NEI scale). [0447] 5.15 Any
preceding method, wherein the lissamine green conjunctival staining
score is in the range of 3 to 5. [0448] 5.16 Any preceding method,
wherein the unanesthetized Schirmer's test score is about 5 mm.
[0449] 5.17 A method for predicting the improvement of visual
function in a subject suffering from dry eye disease
(keratoconjunctivitis sicca) and characterized by a total corneal
fluorescein staining score at least equal or higher than 11 (NEI
scale) at baseline, wherein a decrease of the total corneal
fluorescein staining score (NEI scale) by 3 or more units is
indicative for improvement of visual function. [0450] 5.18 Method
5.17, wherein the subject has at least one eye with a central
corneal fluorescein staining value in the range of 1 to 3 (NEI
scale). [0451] 5.19 Method 5.17 or 5.18, wherein the subject has at
least one eye with a total lissamine green conjunctival staining
score in the range of 2 to 6. [0452] 5.20 Method 5.17 to 5.19,
wherein the subject has at least one eye with an unanesthetized
Schirmer's test score in the range of 4 to 6 mm. [0453] 5.21 Method
5.18 to 5.20, wherein the central corneal fluorescein staining
value is about 3 (NEI scale). [0454] 5.22 Method 5.19 to 5.21,
wherein the lissamine green conjunctival staining score is in the
range of 3 to 5. [0455] 5.23 Method 5.20 to 5.22, wherein the
unanesthetized Schirmer's test score is about 5 mm. [0456] 5.24
Method 5.17 to 5.23, wherein the subject has a total ocular surface
disease index score (OSDI) of equal or greater than 45. [0457] 5.25
Method 5.17 to 5.24, wherein the subject has a total ocular surface
disease index score (OSDI) of equal or greater than 55. [0458] 5.26
Method 5.10 to 5.25, wherein the patient has the total corneal
flueorescein staining score, the central corneal fluorescein
staining value, the lissamine green conjunctival staining score,
and/or the unanesthetized Schirmer's test score with the specified
values in both eyes.
[0459] In a further aspect, the present invention provides for an
ophthalmic composition for use in a method of increasing tear
production volume in a subject, wherein the composition comprises
0.1% w/v cyclosporine dissolved in 1-(perfluorobutyl)pentane. Said
method may comprise a step of topically administering the
composition to an eye of a subject, for example to the surface of
the eye (e.g. the surface of the cornea and/or conjunctiva). The
composition may be administered in the form of a single (i.e. one)
liquid drop per dose. Preferably, the drop volume of said
administered dose is between about 8 to 10 .mu.L. In one embodiment
of said aspect, the composition may be administered twice a day per
eye of the subject. The composition according to said aspect may
comprise of about 0.1% w/v cyclosporine dissolved in
1-(perfluorobutyl)pentane, and optionally, up to about 1.0% w/w of
ethanol. In another embodiment according to this aspect, the
composition for use in said method of increasing tear production
volume in a subject may be a solution consisting of about 0.1% w/v
cyclosporine dissolved in 1-(perfluorobutyl)pentane and about 1.0%
w/w ethanol. In yet a further embodiment according to this aspect,
the composition is a solution consisting of about 0.1% w/v
cyclosporin dissolved in 1-(perfluorobutyl)pentane.
[0460] The ophthalmic composition for use according to this aspect
and any one of its embodiments above may be used in a method of
increasing tear production volume in a subject, wherein the
subject's tear production is suppressed, or presumed to be
suppressed because of ocular inflammation associated with
keratoconjunctivitis sicca. Tear suppression, such as due to ocular
inflammation associated with keratoconjunctivitis sicca in the
subject may for example be determined in a subject based on any one
or combination of the methods as described herein used to assay dry
eye disease signs and symptoms, for example Schirmer type I test or
corneal fluorescein staining, or patient questionnaire.
[0461] In another aspect, the present invention provides for an
ophthalmic composition for use in a method of treating
xerophtalmia, wherein the composition comprises 0.1% w/v
cyclosporine dissolved in 1-(perfluorobutyl)pentane. Preferably
said treatment method increases tear production in the subject. The
method according to said aspect may comprise a step of topically
administering the composition to an eye of a subject, for example
to the surface of the eye (e.g. the cornea and/or conjunctiva). The
composition may be administered in the form of a single liquid drop
per dose; in an embodiment, the volume of the administered drop is
between about 8 to 10 .mu.L. The composition may be administered
twice daily (two times per day) per eye of the subject. In one
embodiment, the composition according to said aspect may comprise
of about 0.1% w/v cyclosporine dissolved in
1-(perfluorobutyl)pentane, and optionally, up to about 1.0% w/w of
ethanol.
[0462] In another embodiment according to this aspect, the
composition for use in said method of treating xerophtalmia,
optionally wherein the method increases tear production in a
subject, is a solution consisting of about 0.1% w/v cyclosporine
dissolved in 1-(perfluorobutyl)pentane and about 1.0% w/w ethanol.
In an alternative embodiment according to this aspect, the
composition is a solution consisting of 0.1% w/v cyclosporin
dissolved in 1-(perfluorobutyl)pentane.
[0463] Damage to the cornea and associated tissues is prevalent in
patients with dry eye disease, in particular those with moderate to
severe, or severe dry eye disease. The tear film, with its lipid,
aqueous and mucin layers normally provides a protective barrier to
corneal tissue and corneal epithelium and has a wetting function
i.e. prevents drying/desiccation. It acts as a conduit for the
provision of oxygen and nutrients to the corneal epithelial cells,
as well as removal of any potential pathogens, debris and waste
products. In patients with dry eye disease, the tear film is
typically unstable or disrupted (for example, as a result of
reduced aqueous secretion or increased evaporation of the tear
film, or reduced secretion of mucin or lipids) and consequently,
the corneal tissue, and conjunctiva may become less protected and
vulnerable and/or prone to damage and deterioration.
[0464] The severity of ocular surface damage which may be
characterized by, for example punctate disruption of the corneal
epithelium or surface disruption of the bulbar conjunctiva, may be
assessed by corneal and conjunctival staining measurements, for
example such as described herein, i.e. fluorescein staining (NEI
scale) and lissamine green staining (Oxford scale), which highlight
and stain in particular, dead or damaged corneal and conjunctival
cells. Particularly, central corneal fluorescein staining (NEI
scale), which assays the central corneal area (as compared to the
peripheral corneal area including inferior, superior, nasal, and
temporal regions of the cornea), reflects ocular surface damage
that impacts visual function impairment.
[0465] As used herein, the term `corneal staining` or `total
corneal staining`, optionally in conjunction with the mention of
fluorescein, or a dye that is suitable or adapted for staining of
the cornea, refers to staining observed as a sum in respect of all
regions of the cornea, i.e. the inferior, superior, central,
temporal, and nasal regions of the cornea. The term `central
corneal staining` or the like (i.e. with specific corneal region
prefacing) and optionally in conjunction with the dye used for
staining, such as fluorescein, refers specifically to staining
observed only in the specified anatomical region.
[0466] As used herein, the term `conjunctival staining` or `total
conjunctival staining`, optionally in conjunction with the mention
of fluorescein or a dye suitable or adapted for staining of the
cornea, refers to staining observed as a sum in respect of all
regions of the conjunctivis, i.e. the temporal and nasal regions of
the conjunctivis. Where the term is used specifying the specific
conjunctival region (e.g. nasal conjunctiva staining), optionally
in conjunction with mention of the dye used for staining, such as
lissamine green, it is to be understood that this refers
specifically to staining observed in said region.
[0467] In one embodiment, the ophthalmic composition for any one of
the uses according to the invention may be used to treat and reduce
the signs of dry eye diseases, in particular treat or reduce ocular
surface damage, such as corneal damage and/or conjunctival damage,
in a subject suffering from dry eye disease. In one embodiment,
said subject to be treated may have ocular surface damage of the
cornea, and have a total corneal fluorescein staining score of at
least equal to, or greater than 10 (.gtoreq.10), the score being
the sum of scores obtained for inferior, superior, central, nasal,
and temporal regions of the cornea, based on the NEI grading scale
of 0-3. In another embodiment, the subject may have a total corneal
fluorescein staining score of at least equal to, or greater than
11, prior to commencement of treatment, optionally wherein the
subject has a total OSDI score of equal to or greater than 45, or
equal or greater than 55.
[0468] In another embodiment, the ophthalmic composition according
to any one of the uses according to the invention may be used to
reduce ocular surface damage, such as corneal damage and/or
conjunctival damage, in a subject suffering from dry eye disease.
In one embodiment, said subject may have a central corneal
fluorescein staining score of at least equal to, or greater than 2
(.gtoreq.2), based on the NEI grading scale of 0-3. In another
embodiment, said subject may in addition also have a total
lissamine green conjunctival staining score (sum of temporal and
nasal regions), based on the Oxford scale, of at least equal to, or
greater than 2 (i.e. .gtoreq.2).
[0469] In one embodiment, the invention relates to an ophthalmic
composition for use in treating i.e. reducing ocular surface damage
in a subject suffering from dry eye disease, wherein said subject
has a total OSDI score of equal, or greater than 45, wherein the
composition comprises about 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane, and optionally up to about 1.0% (w/w) of
ethanol; wherein the composition is administered topically twice
daily, one drop per eye at a drop volume of about 8 to 10 .mu.L. In
another specific embodiment, such use may be for the treatment e.g.
reduction of corneal surface damage, in particular reduction of
ocular surface damage of the central corneal region and/or the
inferior corneal region.
[0470] In a further embodiment, said ophthalmic composition may be
used in the effective treatment of patients with dry eye disease
with signs of corneal ocular surface damage (e.g. with total
corneal staining scores (NEI scale) of at least 11) wherein the
composition is administered twice daily. Said composition may be
topically administered as a single drop per dose and per eye, said
drop having a volume of about 10 .mu.L.
[0471] In another embodiment, the present disclosure relates to an
ophthalmic composition comprising 0.1% (w/v) cyclosporine dissolved
in 1-(perfluorobutyl)pentane for use in: a) a method of treating
and/or ameliorating the symptoms associated with
keratoconjunctivitis sicca (dry eye disease), wherein the symptoms
are dryness, and blurred vision; and/or b) for use in a method of
treating and/or ameliorating the awareness of symptoms of dry eye
disease and the frequency of dryness.
[0472] Optionally, the method of treatment according to said
embodiment comprises topical administration twice daily of a single
drop of the composition per eye, further optionally at a drop
volume of about 8 to 10 .mu.L. In yet a further embodiment, said
composition may consist of 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane and optionally up to 1.0% (w/w) of
ethanol.
[0473] As used herein, the term `severity of dryness` may be used
interchangeably with the term (ocular) `dryness`, which refers to
the symptomatic ocular sensation of dryness which may be
experienced by patients with keratoconjunctivitis sicca (dry eye
disease).
[0474] It has been found that the composition for use as defined
above is surprisingly efficacious in treating, i.e. reducing the
degree of severity in particular in dry eye symptoms selected from
dryness and blurred vision. As noted above, dryness refers to the
ocular sensation of dryness, and is the first question of the VAS
questionnaire as described below. Blurred vision may refer to for
example a certain degree of impaired vision, e.g. objects/text
appear to subjects with blurred vision to be less well-defined or
unclear, or may appear partially obscured. These symptoms may
contribute to overall visual impairment or difficulties, which can
have a negative effect on the subject's performance in functional
tasks where visual performance and acuity may be essential. Thus a
positive and in particular early impact in terms of alleviating and
reducing these symptoms in subjects can be particularly beneficial,
in terms of improving quality of vision and providing relief, and
in particular in subjects for which the discomfort level of these
symptoms is very high and frequent.
[0475] As well as a reduction in severity of dryness and blurred
vision, the present composition according to the invention has also
been found to be effective in reducing the overall degree of
frequency of dryness. A reduction in frequency in which dryness, is
experienced by a subject, and/or reduction in a subject's overall
awareness of dry eye symptoms, may also be beneficial in terms of
improving overall quality of vision and would allow the subject
undertake activities, which may be previously may be severely
limited due to frequent irritation or distraction due to constant
awareness or occurrence of dry eye symptoms.
[0476] The amelioration of these symptoms may be based on, and
determined by application of the visual analog scale (VAS) eye
dryness test, wherein the patients are assessed over the course of
treatment in respect of said symptoms on a scale of 0-100% level of
discomfort, as well as on a scale of 0 to 100%, the percentage of
time in which they are aware of, or experience (i.e. frequency) the
symptoms in their eyes.
[0477] In one embodiment, the compositions for any of the uses of
the present invention are effective in improving by at least 25% a
reduction in the severity of dryness (e.g. ocular dryness) and/or
the frequency of dryness experienced by a patient or subject as
described herein. In another embodiment, the composition is
effective in providing at least a 25% reduction in severity of
dryness and frequency of dryness within 2 weeks of commencement of
the treatment. In another embodiment, the composition is effective
in providing at least a 25% reduction in severity of dryness and
frequency of dryness within 2 weeks of commencement of the
treatment in at least 25% of the subjects undergoing the treatment.
In a further embodiment, the treatment is effective in providing at
least 25% reduction in severity of dryness and/or frequency of
dryness, within 4 weeks of commencement i.e. start of the treatment
in at least 30% of the subjects undergoing the treatment. The
reduction may be determined by comparison of VAS scoring for each
or combination of the above symptoms with initial baseline scores
obtained prior to treatment.
[0478] In further embodiments, the method of treating
keratoconjunctivitis sicca (dry eye disease) may comprise the
topical administration of a composition according to the invention
to an eye, or both eyes of a patient and treating or ameliorating
the frequency of dryness and/or awareness of the symptoms
associated with dry eye disease (e.g. symptoms selected from
dryness, sticky feeling, burning/stinging, foreign body sensation,
itching, blurred vision, sensitivity to light, and pain), wherein
said treatment comprises an effective reduction of the frequency of
dryness or awareness of dry eye symptoms in general, of at least
25%, within 2, or within 4 weeks after the start of treatment.
[0479] Optionally, the ophthalmic composition and dosage thereof as
described herein may be used for treating patients or subjects who
are not responsive, or who are insufficiently responsive to
treatment with aqueous artificial tears.
[0480] Artificial tears, also known as lubricating eye drops or
tear substitutes are used for relief and treatment of the symptoms
of dry eye disease, and which normally may be obtained over the
counter (OTC). These are normally aqueous-based compositions, in
the form of solutions, but also in the form of gels or ointments
which function by adding moisture to the eyes, and usually may
comprise lubricating agents (e.g. hydroxypropyl methyl cellulose
(HPMC), carbomethylcellulose (CMC), polyvinyl alcohol, liquid
polyols such as propylene glycol, polyethylene glycol) and may
contain additives which promote healing (e.g. hyaluronic acid) or
mimic electrolyte composition of natural tear film, or which
promote retention (e.g. gelling agents such as carbomers) of the
composition on the eye surface.
[0481] In an embodiment, the ophthalmic compositions for any one of
the uses according to the invention may be used to treat patients
with persisting dry eye disease symptoms and associated conditions
even following a treatment period with only aqueous artificial
tears over a period of at least 2 weeks, or at least 1 month, or at
least about 6 months.
[0482] A dose of a composition for any one of the uses according to
the present invention and as described in any one of the
embodiments herein is topically administered in the form of a (i.e.
one) single drop to an eye of a subject. The drop may be
administered to the surface of the eye, preferably to any surface
region or tissue of the eye that is accessible to topical
administration or instillation, for example to the cornea or
conjunctiva. The single drop of the composition may be instilled
directly onto a surface of the eye, such as the corneal surface of
the eye, or alternatively into a space i.e. sac or pocket formed by
gently pulling down of the lower eyelid of an eye.
[0483] As used herein, the term `administration to an eye` or `per
eye` refers to the administration of a given dose, e.g. a single
dose, of a ophthalmic composition according to the invention to an
individual eye of a subject. The therapy of the dry eye disease and
dry eye disease associated conditions as described herein however,
should be understood as being not limited to the treatment of a
single eye in a subject, but as being also inclusive of a therapy
involving the administration of compositions according to the
present invention to each i.e. both eyes of a subject which are
affected by the dry eye condition.
[0484] In an embodiment of the invention, the ophthalmic
compositions for any of the uses described herein are administered
at a dose of a single drop two times a day per eye. Thus, a patient
undergoing treatment for both eyes in accordance with such dosing
scheme would receive a total of two drops for each eye on each day
of a given treatment period.
[0485] Where the ophthalmic composition is administered more than
once per day to each eye, for example two times daily per eye, in a
further embodiment, the time interval between topical
administration of the composition to the eye or eye surface of the
first dose and the second dose may be at least 4 hours, or at least
6 hours, or at least 12 hours.
[0486] In a further embodiment, the ophthalmic compositions for any
of the uses of the present invention are administered over a
treatment period of at least 1 month (four weeks), and more at
least 3 months (12 weeks). In another embodiment, the ophthalmic
compositions for any of the uses of the present invention may be
administered on a continuous basis while dry eye disease symptoms
and indicators persist.
[0487] In other embodiments, the ophthalmic compositions for any of
the uses in accordance with the invention may comprise up to about
1.0% (w/w) of ethanol.
[0488] As used herein, the term "up to about" or "up to" used in
context of a parameter, such as presently in relation to the amount
of ethanol in the composition, refers to any value of the parameter
greater than zero and up to, and inclusive of, the defined
parameter. For example, an amount of "up to about 1.0% (w/w) of
ethanol" should be understood as including any value greater than
zero ranging up to and including the value of 1.0% (w/w) of
ethanol, and would include, for example, values such as 0.01%,
0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5% 0.6%, 0.7, 0.8, 0.9, 0.95%,
0.99% (w/w) of ethanol, taking into account any degree of
variability usually observed in measuring or determining this
parameter, using the standard techniques and equipment known in the
relevant field.
[0489] In one embodiment of the invention, the compositions for the
therapeutic uses as described herein may consist essentially of
about 0.1% (w/v) cyclosporine dissolved in
1-(perfluorobutyl)pentane, and optionally about 1.0% (w/w) of
ethanol.
[0490] In another embodiment, the compositions as described herein
are essentially free of ethanol, in which the composition consists
essentially only of cyclosporine in an amount as described in any
of the embodiments described herein dissolved in
1-(perfluorobutyl)pentane.
[0491] The absence of an organic co-solvent such as ethanol may
offer the advantages of a simpler two component formulation
compared to a three component formulation additionally comprising a
co-solvent such as ethanol. The further inclusion, of even one
additional composition component may add complexity in terms of
factors such as cost, manufacturing, handling, packaging, and also
patient compliance.
[0492] In preferred embodiments of the invention, the compositions
for any of the uses as described herein may preferably comprise, or
consist of:
about 0.1% (w/v) of cyclosporine dissolved in
1-(perfluorobutyl)pentane and about 0.5% (w/w) ethanol, or about
0.1% (w/v) cyclosporine dissolved in 1-(perfluorobutyl)pentane and
about 1.0% (w/w) ethanol, or about 0.1% (w/v) cyclosporine
dissolved in 1-(perfluorobutyl)pentane.
[0493] The compositions for any of the uses of the invention are
preferably provided as a clear solution, wherein the cyclosporine
is fully dissolved and in solution in the 1-(perfluorobutyl)pentane
(at room temperature conditions i.e. between 15 to 25.degree. C.).
If ethanol is included, said compositions are also provided as a
clear solution of cyclosporine dissolved and in solution in
1-(perfluorobutyl)pentane and the ethanol. In one embodiment, the
compositions are provided in sterile form.
[0494] In another embodiment, the ophthalmic compositions for any
one of the uses according to the present invention are
substantially free of water and/or substantially free of a
preservative. As understood herein, the term `substantially free`,
or alternatively `essentially free` in reference to a composition
constituent refers to the presence of said constituent in no more
than trace amounts and that if present in trace amounts the
constituent provides no technical contribution to the
composition.
[0495] Preferably, the ophthalmic compositions for any one of the
uses according to the present invention are substantially free of
water, substantially free of a preservative and are effective in
inhibiting microbial growth.
[0496] In another embodiment, the ophthalmic compositions for any
one of the uses according to the present invention are
characterized by a remarkable wetting and spreading behaviour by
which they can rapidly and effectively spread over the surface of
the eye, such as the corneal and/or the conjunctival surface. Thus,
a droplet (drop) of the ophthalmic compositions for any one of the
uses according to the present invention when administered to the
surface of the eye leads to rapid spreading of the compositions
over the corneal and/or the conjunctival surface.
[0497] Preferably, the ophthalmic compositions for any one of the
uses according to the present invention form small droplets
(drops), in the range of about 8-10 .mu.l, such as about 10 .mu.L
when administered from a drop dispenser.
[0498] In another preferred embodiment, the ophthalmic compositions
for any one of the uses according to the present invention are
characterized by the comparable low amount of cyclosporine
administered in a single dose per eye, such as about 10 .mu.g
cyclosporine administered in a single dose per eye, or about 8 to
10 .mu.g of cyclosporin administered in a single dose per eye.
[0499] As used herein, the term "consists" and related terms
"consisting" or "consist" is to be understood as meaning that no
other features, other than those prefaced by the term are present.
In the context of the ophthalmic compositions as described herein,
if any other constituent or component is present in the composition
other than those prefaced by such term, then it is present only in
trace or residual amounts such as to confer no technical advantage
or relevance in respect of the object of the invention, such as may
be further understood by the term `essentially" or "substantially"
used in conjunction with these terms (e.g. `essentially consisting
of").
[0500] The use of an ophthalmic composition as described in any one
of the above embodiments in the manufacture or preparation of a
medicament or a medicine for the treatment of a subject in need
thereof in relation to any one of preferred dry eye disease
conditions described herein are also provided for in the context of
the present invention. Further provided for within the context of
the present invention, are also methods of treating subjects
diagnosed with, and/or suffering from said dry eye disease
conditions as described herein, wherein the methods may comprise
the topical administration, such as by direct topical instillation
to the eye, of any one of the defined compositions, preferably in
any one of the described doses or amounts, and/or over any one of
the defined periods for therapy.
[0501] Said treatment methods and compositions for therapeutic use
are moreover preferably targeted towards human subjects or patients
diagnosed and/or suffering dry eye disease.
[0502] In yet a further aspect, the invention provides also a kit
comprising an ophthalmic composition for any one of the uses
according to the invention and any of the embodiments described
above. In an embodiment, the kit comprises a container for holding
the ophthalmic composition and a drop dispenser adapted for
administering about 8 to 10 .mu.L, or about 10 .mu.l volume of the
composition per drop. The kit may also further comprise
instructions for use, for examples in the form of a leaflet,
packaging or other readable means, indicating use in accordance
with any one of the uses or methods described herein.
[0503] As understood herein, the drop dispenser may be a dispenser
or applicator means which may be mounted, fixed or connected to the
container for holding the ophthalmic composition. Preferably, the
drop dispenser is adapted for dispensing a single dose in the form
of a single drop of the composition. More preferably, the drop
dispenser is adapted for dispensing a single dose of about 8- to
10-.mu.l volume, or is adapted for dispensing a single dose of
about 10-.mu.l volume.
[0504] The container for holding the ophthalmic composition as
understood herein is preferably of a volume which may hold a single
dose, but more preferably of a volume which may hold multiple or a
plurality of doses of the composition.
[0505] The following examples serve to illustrate the invention,
however should not to be understood as restricting the scope of the
invention.
EXAMPLES
Example 1
Study Setup
[0506] A Phase 2b/3, multi-center, randomized, double-masked
(vehicle)-controlled clinical study to assess the efficacy, and
safety and of topical CyclASol.RTM. for treatment of the signs and
symptoms of dry eye disease. The study is listed in
clinicaltrials.gov under the number NCT03292809.
[0507] Subjects eligible to be randomized received one of the
following treatments to dose with bilaterally BID for approximately
85 days (from Visit 1 to Visit 5):
1) CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 0.1%
solution)
2) Vehicle Ophthalmic Solution (F4H5)
[0508] CyclASol 0.1% Ophthalmic Solution is a clear ophthalmic
solution of Cyclosporine A dissolved in 1-(perfluorobutyl)pentane.
1-(perfluorobutyl)pentane, which is commonly abbreviated F4H5 is
used as the vehicle. The only other component in the formulation is
ethanol 1.0% (w/w) as co-solvent. The administered dose of
CyclASol, i.e. a single drop has a volume of about 8-10 .mu.L.
[0509] A 14-day study-run-in period was used for subject selection
before randomization. During this period, all subjects received
Systane.RTM. Balance to dose with bilaterally BID.
[0510] The study involved 6 visits over the course of approximately
14 weeks:
Visit 0, -Day -14.+-.2 days, Screening;
Visit 1, Day 1, Baseline/Randomization;
[0511] Visit 2, Day 15.+-.1 days, 2-Week Follow-Up; Visit 3, Day
29.+-.2 days, 4-Week Follow-Up; Visit 4, Day 57.+-.2 days, 8-Week
Follow-Up; and Visit 5, Day 85.+-.2 days, 12-Week Follow-Up and
Study Exit.
Study Population
[0512] Patients included in the study had to fulfill following
criteria: [0513] (a) Be at least 18 years of age; [0514] (b)
Provide written informed consent; [0515] (c) Have a subject
reported history of Dry Eye Disease in both eyes for at least 180
days before Visit 0; [0516] (d) Be currently using (within 30 days
before Visit 0) over-the-counter (OTC) eye drops and/or artificial
tears for dry eye symptoms at Visit 0; [0517] (e) Have a total
OSDI.RTM. score of .gtoreq.20 at Visit 0 and Visit 1; [0518] (f)
Have a total corneal fluorescein staining score of .gtoreq.10 (i.e.
sum of inferior, superior, central, nasal, and temporal regions)
according to the NEI scale at Visit 0 and Visit 1; [0519] (g) Have
a total lissamine green conjunctival score (sum of temporal and
nasal regions) of .gtoreq.2 according to the Oxford scale at Visit
0 and Visit 1; [0520] (h) Have an unanesthetized Schirmer's Test
score between 1 mm and 10 mm inclusive at Visit 0 and Visit 1;
[0521] (i) Have at least one eye, the same eye, satisfy inclusion
criteria f, g, and h; and [0522] (j) Be able and willing to follow
instructions and participate in all study assessments and
visits.
[0523] Each subject must not: [0524] a. Have any clinically
significant slit-lamp findings at Visit 0 that require prescriptive
medical treatment and/or in the opinion of the investigator may
interfere with study parameters including trauma, Steven Johnson
Syndrome, advanced epithelial basement membrane disease; [0525] b.
Have active blepharitis, meibomian gland dysfunction (MGD) or lid
margin inflammation that required any topical or systemic
antibiotics or topical steroids or other prescription medical
treatment or treatment with hypochlorous acid wipes within last 30
days prior to Visit 0 or will require such treatment during the
study. Any other therapy such as lid scrubs, lid wipes, warm
compresses have to be stable within the last 30 days prior to Visit
0 and the subject should be willing to continue those therapies
through the study; [0526] c. Have abnormal lid anatomy (e.g.
incomplete eyelid closure, entropion, or ectropion) or abnormal
blinking; [0527] d. Have Dry Eye Disease secondary to scarring
from, for example, irradiation, alkali burns, cicatricial
pemphigoid, or conjunctival goblet cell destruction (i.e.
conjunctival goblet cell destruction because of vitamin A
deficiency); [0528] e. Have an ocular or periocular malignancy;
[0529] f. Have any corneal epithelial defect, or have in more than
2 of the 5 corneal regions >50% confluent corneal staining;
[0530] g. Have a history of herpetic keratitis; [0531] h. Have
active ocular allergies or ocular allergies that may become active
during the study period; [0532] i. Be diagnosed with an ongoing
ocular or systemic infection (bacterial, viral, or fungal),
including a fever, or be undergoing treatment with antibiotics at
Visit 0 or Visit 1; [0533] j. Have worn contact lenses within 90
days before Visit 0 or anticipate using contact lenses during the
study; [0534] k. Have used any eye drops, gels or scrubs within 2
hours before Visit 0 or Visit 1; [0535] l. Have used topical
Cyclosporine A (CsA) or Lifitegrast within 60 days before Visit 0;
[0536] m. Have participated in a previous CyclASol study (patients
who were assigned to the Restasis treatment arm may enter the
study); [0537] n. Have had intraocular surgery or ocular laser
surgery within 180 days before Visit 0, or have any planned ocular
or eyelid surgeries during the study period; [0538] o. Be a woman
who is pregnant, nursing, or planning a pregnancy; [0539] p. Be
unwilling to submit a urine pregnancy test at Visit 0 and Visit 5
(or early termination visit) if of childbearing potential.
Non-childbearing potential is defined as a woman who is permanently
sterilized (i.e. has had a hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy), or is post-menopausal (i.e. without
menses for 12 consecutive months); [0540] q. Be a woman of
childbearing potential who is not using an acceptable means of
contraception. Acceptable methods of contraception include hormonal
contraceptives (i.e. oral, implantable, injectable, or transdermal
contraceptives), mechanical contraceptives (i.e. spermicide in
conjunction with a barrier such as a diaphragm or a condom),
intrauterine devices (IUD), or the surgical sterilization of the
partner. For non-sexually active females, abstinence may be
regarded as an adequate method of birth control; however, if the
subject becomes sexually active during the study, she must agree to
use adequate birth control as defined above for the remainder of
the study; [0541] r. Have an uncontrolled systemic disease; [0542]
s. Have a known allergy or sensitivity to the study drug or its
components: Cyclosporine A (CsA) or semifluorinated alkanes (SFA);
[0543] t. Have active ocular or periocular rosacea or a pterygium;
[0544] u. Be currently enrolled in an investigational drug or
device study or have used an investigational drug or device within
60 days before Visit 0; [0545] v. Have used any topical
antiglaucoma medications within 90 days before Visit 0; [0546] w.
Have used any topical ocular or facial steroids, or serum tears, or
oral doxycycline, or oral tetracycline within 30 days before Visit
0; [0547] x. Have used systemic steroids (including dermatological
steroids with high potency or large treatment areas) or
immunomodulating agents on a non-stable regimen within 90 days
before Visit 0 or anticipate their use on a non-stable regimen
during the study period; [0548] y. Have used any oral medications
known to cause ocular drying (e.g. antihistamines or
antidepressants) on a non-stable regimen within 30 days before
Visit 0 or anticipate non-stable use of oral ocular-drying
medication during the study; [0549] z. Have a corrected visual
acuity greater than or equal to log MAR+0.7 as assessed by the
Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in
either eye at Visit 0 or Visit 1; [0550] aa. Have a condition or be
in a situation (e.g. language barrier) which the investigator feels
may put the subject at significant risk, may confound the study
results, or may interfere with the subject's participation in the
study significantly; or [0551] bb. Have received or removed a
punctal plug within 90 days before Visit 0 or anticipate the
implant or removal of a punctal plug during the study.
[0552] The full analysis set of patients were, respectively, 162
for CyclAsol 0.1% treatment and 166 for vehicle treatment.
[0553] At baseline, the CyclAsol 01.% group of patients had the
following characteristic: a mean total corneal fluorescein staining
NEI scale (SD) of 11.5 (1.26); a mean central corneal fluorescein
staining NEI scale (SD) of 2 (0.51); a mean conjunctival staining
of 4.1 (1.70); a mean total OSDI (SD) of 46.9 (16.73); a VAS
severity of dryness (SD) of 68.5 (21.6); a mean Schirmer test score
of 5.2 (2.83).
[0554] At baseline, the vehicle group of patients had the following
characteristics: a mean total corneal fluorescein staining NEI
scale (SD) of 11.5 (1.25); a mean central corneal fluorescein
staining NEI scale (SD) of 2 (0.52); a mean conjunctival staining
of 4.3 (1.66); a mean total OSDI (SD) of 47.1 (16.41); a VAS
severity of dryness (SD) of 69.9 (20.5); a mean Schirmer test score
of 5.1 (2.64).
Instructions for Use
[0555] Subjects were instructed to instill one drop of treatment 1)
or 2) in each lower eyelid two times daily (in the morning and in
the evening before bed).
Evaluation Criteria
[0556] At each visit during the treatment period, each subject was
assessed in terms of treatment efficacy using tests including:
corneal fluorescein staining (NEI Grading); conjunctival staining
(Lissamine, Oxford grading), as well as subject symptom assessment
questionnaires such as Ocular Surface Disease Index questionnaire
(OSDI, ref. Schiffman R. M. et al 2000; 118:615-621.) and visual
analogue scale (VAS).
[0557] The following efficacy measures were obtained during the
study:
Primary Efficacy Measures
[0558] The following primary endpoints were tested in order using
hierarchical fixed sequence testing: [0559] 1. Change from baseline
in total Corneal fluorescein staining (NEI scale) at Day 29. [0560]
2. Change from baseline in Ocular Surface Disease Index (OSDI) at
Day 29. Key Secondary Efficacy Measures included: [0561] Total
Corneal fluorescein staining (NEI scale) and change from baseline
to each measured post-baseline visit (other than Day 29) [0562]
Ocular Surface Disease Index (OSDI) and change from baseline to
each measured post-baseline visit (other than Day 29) [0563]
Lead/Worst symptom assessment [0564] Reading impairment score and
change from baseline to each measured post-baseline visit [0565]
Unanesthetized Schirmer's Test and change from baseline to each
measured post-baseline visit [0566] Central and inferior corneal
staining (NEI scale) and changes from baseline to each measured
post-baseline visit
Secondary Efficacy Measures:
[0566] [0567] Reading assessment and change from baseline to each
measured post-baseline visit [0568] Corneal fluorescein staining
other sub-regions (NEI scale) and changes from baseline to each
measured post-baseline visit [0569] Ocular Surface Disease Index
(OSDI) subtotal scores and changes from baseline to each measured
post-baseline visit [0570] Conjunctival lissamine green staining by
region and total (Oxford scale) and changes from baseline to each
measured post-baseline visit [0571] Tear film break-up time (TFBUT)
and change from baseline to each measured post-baseline visit
[0572] Visual analog scale (VAS) and changes from baseline for
severity of: dryness, burning/stinging, sticky feeling, foreign
body sensation, itching, blurred vision, sensitivity to light, pain
and for awareness of dry eye symptoms and frequency of dryness to
each measured post-baseline visit [0573] InflammaDry.RTM. test
(MMP-9) and change from baseline to each measured post-baseline
visit [0574] Symptoms as recorded in subject diary to each measured
post-baseline visit
Corneal Staining
[0575] For corneal staining (Sook Chun Y et al., Am J Ophthalmol.
2014 May; 157(5):1097-102), 5 .mu.l of 2% preservative-free sodium
fluorescein solution was instilled into the inferior conjunctival
cul-de-sac of each eye. In order to achieve maximum fluorescence,
the fluorescein staining is evaluated only after approximately 3-5
minutes after instillation. A Wratten #12 yellow filter was used to
enhance the ability to grade fluorescein staining.
[0576] The staining was graded with the NEI Grading Scale (The
National Eye Institute grading system), with only the cornea being
graded. Corneal fluorescein staining scores were obtained for each
of the inferior, superior, central, temporal, and nasal regions of
the cornea based on a 0-3 scale, where a score of 0 means no
staining is observed. The term "total corneal fluorescein staining
total score" refers to a sum of scores from the inferior, superior,
central, temporal, and nasal regions of the cornea.
Conjunctival Lissamine Green Staining
[0577] Conjunctival Lissamine Green Staining (Bron A. J. et al,
Cornea. 2003; 22:640-650) was conducted by instillation of 10 .mu.l
of lissamine green solution into the inferior conjunctival
cul-de-sac of a subject. After waiting for approximately 30 seconds
the staining was evaluated. The subject was instructed to blink
several times to distribute the lissamine green. The staining was
graded with the Oxford Grading Scale. Herein, the lissamine
staining is represented by punctate dots on a series of panels
(A-E). Staining ranges from 0-5 for each panel and 0-10 for the
total exposed inter-palpebral conjunctiva. Both nasal and temporal
regions were graded separately. A score of 0 means no staining.
Total conjunctival lissamine green staining scores were obtained,
referring to the sum of scores from both temporal and nasal regions
of the conjunctiva.
Ocular Surface Disease Index (OSDI)
[0578] Ocular Surface Disease Index (OSDI) (ref. Schiffman R M, et
al., Arch Ophthalmol. 2000; 118:615-621) is a survey tool used for
the assessment of symptoms of ocular irritation in dry eye disease
and how they affect functioning related to vision. It is a 12-item
questionnaire assessing dry eye symptoms and effects on
vision-related function in the past week of a patient's life. The
questionnaire has 3 subscales: ocular symptoms, vision-related
function, and environmental triggers. Patients rate their responses
on a 0 to 4 scale with 0 corresponding to "none of the time" and 4
corresponding to "all of the time." A final score is calculated
which ranges from 0 to 100.
[0579] The questions assess dry eye symptoms experienced by the
patient within past week including the following: sensitivity to
light, gritty sensation, pain or sore eyes, blurriness, and poor
vision; vision-related function, in terms of problems in: reading,
driving at night, working on a computer or bank machine, watching
television; and in terms of environmental factors or triggers i.e.
discomfort during: windy conditions, places with low humidity, and
areas with air condition. Subtotals are obtained for all the
questions, as well as the total number of questions answered. The
OSDI index is assessed based on a scale of 0 to 100, with higher
scores representing a greater disability. The OSDI index is
calculated from the sum of the scores multiplied by a factor of 25,
over the total number of questions answered.
Visual Analog Scale (VAS)
[0580] Subjects were asked to rate their ocular symptoms (both eyes
simultaneously) due to ocular dryness in a 10-item questionnaire
and asked to place a vertical mark on the horizontal line starting
at the value of 0%, corresponding to no discomfort, and ending at a
value of 100%, corresponding to maximal discomfort, to indicate the
level of discomfort. Subjects were asked about the each of
following: dryness (corresponding to the first question in the VAS
questionnaire, and also referred to in the text and in the graphs
as severity of dryness), sticky feeling (question 2),
burning/stinging (question 3), foreign body sensation (question 4),
itching (question 5), blurred vision (question 6), sensitivity to
light (question 7), and pain (question 8). Subjects were also asked
about their awareness of their dry eye symptoms (question 9) and
frequency of dryness (question 10), in terms of the percentage of
time. For these two questions, the value of 0% corresponds to
`never` and a value of 100% corresponds to "all of the time". The
assessment line length of the scale is 100 mm (10 cm), with grading
provided at every 10 mm (suggesting 10%, 20%, etc).
[0581] A comparison may be made between the values indicated by the
patient at each visit, compared to baseline values at Day 1 visit
1, to determine the effectiveness of treatment.
Schirmer's Test I (without Anesthesia)
[0582] Schirmer Tear Test I is performed according to the following
procedure. Do not blot prior to the test. Using a sterile Tear Flo
Schirmer test strip, a bend in the strip is made in line with the
notch in the strip. The subject is instructed to gaze up and in.
The Schirmer test strip is placed in the lower temporal lid margin
of each eye such that the strip fits tightly. Subjects were
instructed to close their eyes. After 5 minutes have elapsed, the
Schirmer strip was removed. The length of the moistened area was
recorded (mm) for each eye.
Tear Film Break-up Time (TFBUT)
[0583] The examiner instilled 5 .mu.L of 2% preservative-free
sodium fluorescein solution into the inferior conjunctival
cul-de-sac of each eye. To thoroughly mix the fluorescein with the
tear film, the subject was instructed to blink several times. In
order to achieve maximum fluorescence, the examiner should wait
approximately 30 seconds after instillation before evaluating
TFBUT.
[0584] With the aid of a slit-lamp, the examiner monitored the
integrity of the tear film, noting the time it takes to form
micelles from the time that the eye is opened. TFBUT was measured
in seconds using a stopwatch and a digital image recording system
for the right eye followed by the left eye. A Wratten #12 yellow
filter was used to enhance the ability to grade TFBUT.
[0585] For each eye, two measurements were taken and averaged
unless the two measurements are >2 seconds apart and are each
<10 seconds, in which case, a third measurement would be taken
and the two closest of the three would be averaged. All values were
recorded in the source document.
Study Results
[0586] It was observed that treatment with CyclAsol in dry eye
disease patients, having at baseline a total OSDI score of equal,
or greater than 45 (.gtoreq.45) obtained at the first visit
(baseline score) was particularly effective (FIG. 1). It was
observed that there was a significant change from the baseline of
the total OSDI during the treatment. In particular, and compared
with the vehicle, CyclAsol also has a remarkable effect in the
group of patients having a total OSDI .gtoreq.55 at baseline (FIG.
2).
[0587] It is also observed, compared to the general population of
patients in the study, the mean change from baseline of total OSDI
over the 12-week course of treatment with Cyclasol was generally
more significant for patients having an OSDI .gtoreq.45 or
.gtoreq.55.
[0588] It was also found that compared to the vehicle, that the
overall awareness and frequency of the symptoms of dry eye disease,
assessed using the dry eye symptom visual analog scale (VAS) test,
was significantly reduced, compared to baseline visit scoring,
already after only 4 weeks duration of treatment with CyclASol
(FIG. 3).
[0589] For the severity of dryness, which corresponds to the
question relating to the symptom of "dryness" in the VAS
questionnaire, it was also observed that the mean change from
baseline was significant, at already 4 weeks of treatment in terms
of a reduction in the level of severity of dryness. The baseline
values for VAS severity of dryness were 68.5 and 69.9 for CyclAsol
0.1% and vehicle, respectively.
[0590] Similarly, a reduction in the severity of blurred vision,
which is assessed as part of the VAS (visual analog scale) test was
also observed. At primary endpoint visit a statistically
significant (p=0.02-0.03) symptoms improvement was shown for the
symptoms shown in FIG. 3.
[0591] It was also found, that the proportion of patients in the
study having at least 25% or higher improvement (compared to
baseline visit values), in terms of a reduction in the severity of
dryness as determined by the VAS test was higher for CyclASol at
all visits compared to the vehicle. The proportion of patients with
a response rate of 25% or higher from treatment with CyclASol, with
respect to a reduction in severity of dryness, was about 26%,
already at week 2 of the treatment. At 4 weeks, at 8 weeks and at
12 weeks, the percentage of patients with a response rate of 25% or
higher, that is with an improvement of 25% or more, for the
reduction in severity of dryness was observed to be 33% 37% and
39%, respectively. Similarly, it was observed that the responder
rate for the reduction in the frequency of dryness experienced by
the patients, in terms of patients having 25% or higher degree of
improvement (compared to baseline visit values), as determined by
the VAS testing, was also higher for the CyclASol treatment
compared to the vehicle. The proportion of patients with a response
rate of 25% or higher from treatment with CyclASol, with respect to
a reduction in the frequency of dryness, was 24%, already at week 2
of the treatment. At 4 weeks, at 8 weeks and at 12 weeks, the
percentage of patients with a response rate of 25% or higher for
the reduction in frequency of dryness was observed to be 34%, 42%
and 37%, respectively.
[0592] The primary endpoint of the study at 4 weeks was met with
high statistical and clinical significance, as shown in FIGS. 5 and
6. The onset of effect on the total corneal fluorescein staining
was as early as two weeks and was sustained during the entire study
duration (FIG. 5). The mean baseline value for tCFS for CyclAsol
0.1% and vehicle was 11.5 for both groups. As shown in FIG. 6, more
than 50% of all patients responded to CyclAsol 0.1% with an
improvement of .gtoreq.3 grades in total corneal fluorescein
staining after 4 weeks of treatment.
[0593] The region of the cornea which benefited most of the
CyclAsol 0.1% treatment was the central area, which is the most
important region for visual function. As shown in FIG. 7, an
improvement in central corneal fluorescein staining .gtoreq.1 grade
was obtained in 58.6% of the subjects undergoing CyclAsol 0.1%
treatment after 4 weeks treatment.
[0594] A high responder rate was obtained also on conjunctiva. In
FIG. 8 it is shown that after 12 weeks treatment, 50.3% of the
patients undergoing CyclAsol 0.1% treatment improved of at least 2
grades in conjunctival lissamine green staining score, which is a
sign relevant for ocular health. FIG. 9 shows the change from
baseline of the conjunctival lissamine green staining in the two
patients populations. The baseline values for the CyclAsol 0.1%
group and vehicle group are respectively 4.1 and 4.3.
* * * * *